Novel substituted diamine derivatives useful as motilin antagonists

ABSTRACT

The present invention relates to novel substituted diamine derivatives for the formula  
                 
 
wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , A, Y and n are as described in the specification, pharmaceutical compositions containing them and intermediates used in their manufacture. More particularly, the compounds of the invention are motilin receptor antagonists useful for the treatment of associated conditions and disorders such as gastrointestinal reflux disorders, eating disorders leading to obesity and irritable bowel syndrome.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional application Ser.No. 60/202,131 filed May 05, 2000, the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted diamine derivatives,pharmaceutical compositions containing them and intermediates used intheir manufacture. More particularly, the compounds of the invention aremotilin receptor antagonists useful for the treatment of associatedconditions and disorders such as gastrointestinal reflux disorders,eating disorders leading to obesity and irritable bowel syndrome.

BACKGROUND OF THE INVENTION

In mammals, the digestion of nutrients and the elimination of waste arecontrolled by the gastrointestinal system. Within this system, there area number of natural peptides, ligands, enzymes, and receptors which playa vital role and are potential targets for drug discovery. Modifying theproduction of, or responses to these endogenous substances can have aneffect upon the physiological responses such as diarrhea, nausea, andabdominal cramping. One example of an endogenous substance which affectsthe gastrointestinal system is motilin.

Motilin is a peptide of 22 amino acids which is produced in thegastrointestinal system of a number of species. Although the sequence ofthe peptide varies from species to species, there are a great deal ofsimilarities. For example, human motilin and porcine motilin areidentical; while motilin isolated from the dog and the rabbit differ byfive and four amino acids respectively. Motilin induces smooth musclecontractions in the stomach tissue of dogs, rabbits, and humans as wellas in the colon of rabbits. Apart from local gastrointestinal intestinaltissues, motilin and its receptors have been found in other areas. Forexample motilin has been found in circulating plasma, where a rise inthe concentration of motilin has been associated with gastric effectswhich occur during fasting in dogs and humans. Itoh, Z. et al. Scand. J.Gastroenterol. 11:93-110, (1976); Vantrappen, G. et al. Dig. Dis Sci 24,497-500 (1979). In addition, when motilin was intravenously administeredto humans it was found to increase gastric emptying and gut hormonerelease. Christofides, N.D. et al. Gastroenterology 76:903-907, 1979.

Aside from motilin itself, there are other substances which are agonistsof the motilin receptor and which elicit gastrointestinal emptying. Oneof those agents is the antibiotic erythromycin. Even though erythromycinis a useful drug, a great number of patients are affected by the drug'sgastrointestinal side effects. Studies have shown that erythromycinelicits biological responses that are comparable to motilin itself andtherefore may be useful in the treatment of diseases such as chronicidiopathic intestinal pseudo-obstruction and gastroparesis. Weber, F. etal., The American Journal of Gastroenterology, 88:4, 485-90 (1993).

Although motilin and erythromycin are agonists of the motilin receptor,there is a need for antagonists of this receptor as well. The nausea,abdominal cramping, and diarrhea which are associated with motilinagonists are unwelcome physiological events. The increased gut motilityinduced by motilin has been implicated in diseases such as IrritableBowel Syndrome and esophageal reflux. Therefore researchers have beensearching for motilin antagonists.

One such antagonist is OHM-11526. This is a peptide derived from porcinemotilin which competes with both motilin and erythromycin for themotilin receptor in a number of species, including rabbits and humans.In addition, this peptide is an antagonist of the contractile smoothmuscle response to both erythromycin and motilin in an in vitro rabbitmodel. Depoortere, I. et al., European Joumal of Pharmacology, 286,241-47, (1995). Although this substance is potent in that model (IC₅₀1.0 nM) it is a peptide and as such offers little hope as an oral drugsince it is susceptible to the enzymes of the digestive tract. Zen Itoh,Motilin, xvi (1990). Therefore it is desirable to find othernon-peptidic agents which act as motilin antagonists. The compounds ofthis invention are such agents.

The compounds of this invention are non-peptidyl motilin antagonistswith potencies and activities comparable to known peptidyl motilinantagonists. These compounds compete with motilin and erythromycin forthe motilin receptor site in vitro. In addition, these compoundssuppress smooth muscle contractions induced by motilin and erythromycinwith activities and potencies comparable to OHM 11526 in an in vitromodel.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula (I):

wherein

R¹ is selected from the group consisting of hydrogen, aryl, aralkyl,heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and lower alkyl; whereinthe alkyl, aryl or heterocyclyl moieties in the foregoing groups may besubstituted with one or more substituents independently selected fromhalogen, hydroxy, nitro, carboxy, cyano, amino, dialkylamino, loweralkoxy, lower alkyl, tri-halomethyl, alkylamino, carboxy andalkoxycarbonyl;

R² is selected from the group consisting of aryl, aralkyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, diarylalkyl,aminoalkyl, tri-halomethyl, arylamino and lower alkyl; wherein thealkyl, aryl, heterocyclyl-alkyl, heterocyclyl, or amino moieties in theforegoing groups may be substituted with one or more substituentsindependently selected from halogen, hydroxy, nitro, cyano, amino,dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, alkylamino,phenyl, carboxy, carboxyalkyl and alkoxycarbonyl;

X 1, X², X³ and X⁴ are independently absent or selected from the groupconsisting of CO and SO₂; provided that at least one of X¹ or X² and atleast one of X³ or X⁴ is CO or SO₂;

alternatively R^(1, R) ² and X¹ can be taken together (with the aminenitrogen) to form a monocyclic or fused bicyclic or tricyclic secondaryamine ring structure; wherein the monocyclic or fused bicyclic ortricyclic secondary amine ring structure may be optionally substitutedwith one or more substituents independently selected from halogen, oxo,nitro, cyano, amino, alkylamino, dialkylamino, trialkylamino, loweralkoxy, lower alkyl, tri-halomethyl, carboxy, acetyloxy, alkoxycarbonyl,aryl, aralkyl andr heterocyclyl;

A is selected from the group consisting of lower alkyl, lower alkenyl,cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, cycloalkenyl,cycloalkenyl-alkyl, alkyl-cycloalkenyl, alkyl-cycloalkyl-alkyl;alkyl-aryl-alkyl, alkyl-aryl, aryl-alkyl and phenyl; where, in eachcase, the A group may optionally be substituted with one or moresubstituents selected from R⁷;

where R⁷ is selected from alkyl, tri-halomethyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heterocyclyl-alkyl, diarylalkyl, aminoalkyl, orarylamino; wherein the alkyl, aryl, heterocyclyl-alkyl, heterocyclyl, oramino moieties in the foregoing groups may be substituted with one ormore substituents independently selected from halogen, hydroxy, nitro,cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl,alkylamino, phenyl, carboxy and alkoxycarbonyl;

provided that A is not -1,3-cyclopentyl-1-ene-alkyl;

R³ is selected from the group consisting of hydrogen, aryl,heterocyclyl, aralkyl, diarylalkyl, heterocyclo-alkyl, tri-halomethyl,alkylamino, arylamino and lower alkyl; wherein the aryl, heterocyclyl,aralkyl, diarylalkyl, heterocyclyl-alkyl, alkylamino, arylamino or loweralkyl group may be substituted with one or more substituentsindependently selected from halogen, nitro, cyano, amino, dialkylamino,lower alkoxy, lower alkyl, tri-halomethyl, carboxy and alkoxycarbonyl;

Y is selected from the group consisting of —O—, —NH—, —S—0 and 13 SO₂—;

n is an integer from 0 to 5;

R⁴ is selected from the group consisting of hydrogen, amino, alkylamino,dialkylamino, N-alkyl-N-aralkyl-amino, trialkylamino,dialkylaminoalkoxyalkyl, heterocyclyl, heterocyclyl-alkyl,oxo-substituted heterocyclyl and lower alkyl-substituted heterocyclyl;

R⁵ is selected from the group consisting of hydrogen, halogen, nitro,cyano, amino, alkylamino, dialkylamino, trialkylamino, lower alkoxy,lower alkyl, tri-halomethyl, carboxy and alkoxycarbonyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

DETAILED DESCRIPTION OF THE INVENTION

Relative to the above generic description, certain compounds of thegeneral formula are preferred.

where p and t are integers from 1-6. More preferably, R⁴ is selectedfrom the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl,2-oxo-pyrrolidin-1-yl, 2-(1-methylpyrrolidinyl), 1-piperazinyl,1-piperidinyl, di(methyl)aminoethyloxyethyl, N-methyl-N-benzyl-amino,di(methyl)amino and diethylamino. More preferably still, R⁴ is selectedfrom the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl,1-piperazinyl, 1-piperidinyl, di(methyl)amino and di(ethyl)amino. Morereferably still, R⁴ is selected from the group consisting of hydrogen,4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino. Mostpreferably, R⁴ is selected from the group consisting of hydrogen,4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl;

Preferably R⁵ is selected from the group consisting of hydrogen andlower alkyl. More preferably R⁵ is selected from the group consisting ofhydrogen and methyl.

In a preferred embodiment of the present invention are those compoundsof general formula (I) wherein:

R¹ is selected from the group consisting of hydrogen, aralkyl,heterocyclyl and heterocyclyl-alkyl; where the aralkyl, heterocyclyl orheterocyclyl-alkyl may be substituted with one or more substituentsindependently selected from halogen, lower alkyl, lower alkoxy,tri-halomethyl, hydroxy or nitro;

R² is selected from the group consisting of alkyl, tri-halomethyl, aryl,aralkyl, arylamino, biphenyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyland heterocyclyl-alkyl; where the aryl, aralkyl or heterocyclyl groupmay be substituted with one or more substituents independently selectedfrom halogen, lower alkoxy, nitro, carboxy, carboxyalkyl, hydroxy,phenyl, diphenylmethyl, tri-halomethyl or trihaloalkylacetyl;

X¹, X², X³ and X⁴ are independently absent or selected from the groupconsisting of CO and SO₂; such that at least one of X¹ or X² and atleast one of X³ or X⁴ is CO or SO₂;

A is selected from the group consisting of lower alkyl,alkyl-cycloalkyl, cycloalkyl-alkyl, -cycloalkyl, -cycloalkenyl-,cycloalkenyl-alkyl- and -aryl-alkyl-; where the alkyl moiety in theforegoing groups may be substituted with one or more substituentsindependently selected from aralkyl or cycloalkyl;

provided that A is not -1,3-cyclopentyl-1-ene-alkyl;

R³ is selected from the group consisting of hydrogen, aryl, aralkyl andarylamino; where the aryl or aralkyl group may be substituted with oneor more substituents independently selected from halogen, lower alkyl,lower alkoxy or tri-halomethyl;

Y is —O—;

n is an integer from 0 to 3;

R⁴ is selected from the group consisting of hydrogen, heterocyclyl,oxo-substituted heterocyclyl, lower alkyl-substituted heterocyclyl,di(lower alkyl)amino, N-lower alkyl-N-aralkyl-amino and di(loweralkyl)amino alkoxy alkyl;

R⁵ is selected from the group consisting of hydrogen and lower alkyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

In a preferred embodiment are compounds of the general formula (I)wherein:

R¹ is selected from the group consisting of hydrogen, phenyl (C₁-C₆)alkyl-, naphthyl(C₁₋₆)alkyl and heterocyclyl (C₁-C₆)alkyl- where theheterocyclyl group is selected from pyridyl and where the phenyl,naphthyl or heterocyclyl moiety is optionally substituted with one tothree substituents selected from halogen, lower alkyl, lower alkoxy,tri-halomethyl, hydroxy and nitro;

R² is selected from the group consisting of (C₁-C₆)branched orunbranched alkyl, phenyl, phenyl(C₁-C₆)alkyl-, tri-halomethyl,phenylamino-, biphenyl, diphenyl(C_(l-C) ₆)alkyl-, C₅₋₈cycloalkyl,C₅₋₈cycloalkyl-alkyl,heterocyclyl and heterocyclyl(C₁-C₆)alkyl- whereinthe heterocyclyl moiety is selected from naphthyl, furyl, pyridyl,pyrrolidinyl and thienyl and wherein the phenyl or heterocyclyl groupmay be substituted with one to four substitutuents selected fromhalogen, lower alkoxy, nitro, carboxy, carboxy(C₁₋₄)alkyl, hydroxy,phenyl, diphenylmethyl, trihalomethyl and trihaloalkylacetyl;

X¹, X², X³ and X⁴ are independently absent or selected from the groupconsisting of CO and SO₂; such that at least one of X¹ or X² and atleast one of X³ or X⁴ is CO or SO₂;

A is selected from the group consisting of lower alkyl,loweralkyl-cycloalkyl, cycloalkyl-loweralkyl, -cycloalkyl,-cycloalkenyl-, cycloalkenyl-loweralkyl- and -phenyl-loweralkyl- and-benzyl-loweralkyl, provided that A is not -1,3-cyclopentyl-1-ene-alkyl;

R³ is selected from the group consisting of hydrogen, phenyl, benzyl andphenylamino-; where the phenyl or benzyl moieties may be substitutedwith one to three substituents selected from halogen, lower alkyl, loweralkoxy and trihalomethyl;

Y is —O—;

n is an integer from 0 to 3;

R⁴ is selected from the group consisting of hydrogen, heterocyclyl, oxosubstituted heterocyclyl, lower alkyl-substituted heterocyclyl,di(loweralkyl) amino, N-lower alkyl-N-aralkyl-amino and a moiety of theformula:

where p and t are integers from 1-6;

R⁵ is selected from hydrogen and lower alkyl;

and the pharmaceutically acceptable salts esters and pro-drug formsthereof.

In a more preferred embodiment of the present invention are compounds ofthe general formula (I) wherein

Ris selected from the group consisting of hydrogen, benzyl,2-(phenyl)ethyl, 4-methylbenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-chlorobenzyl, 3-fluorobenzyl, 4-chlorobenzyl, 2,3-dichlorobenzyl,3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 3,4-difluorobenzyl,3-trifluoromethylbenzyl, 1-naphthyl-methyl, 2-pyridyl-methyl and 4-(l-hydroxy)pyridyl;

R² is selected from the group consisting of methyl, ethyl, t-butyl,2,2-dimethylpropyl, benzyl, 2-(phenyl)ethyl, 3-(phenyl)propyl,1-(phenyl)propyl, 3-carboxy -n-propyl, 3-carboxy-3-methyl-n-butyl,2,2-dimethyl-3-carboxy-n-propyl, trichloromethyl, trifluoromethyl,2-naphthyl, phenylamino, 3-methoxyphenyl, 3-hydroxyphenyl,4-fluorobenzyl, 3-carboxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2-(4-methoxyphenyl)ethyl, 4-fluorophenyl,2-(4-chlorophenyl)ethyl, 3-nitrophenyl, 3,5-di(trifluoromethyl)phenyl,3,3,3-trifluoropropan-2-oyl, diphenylmethyl, 4-biphenyl,3-carboxymethyl-1,2,2-trimethyl-cyclopentyl, cyclopentylethyl,(1-carboxymethyl-cyclopentyl)-methyl, 2-furyl, 2-pyridyl-(2-ethyl),1-pyrrolidinyl-(2-ethyl), 2-theinylmethyl and 2-thienylethyl;

X¹, X², X³ and X⁴ are independently absent or selected from the groupconsisting of CO and SO₂; such that one of X¹ or X² and one of X³ or X⁴is CO or SO₂;

A is selected from the group consisting of 1,2-ethyl, 1,3-propyl,1,4-butyl, 2-methyl-1,3-propyl, 1,1, -dimethyl-(1,3-propyl),2-cyclopentyl-1,3-n-propyl, 1S,3R-cyclopentyl -methyl,1,2-cyclopent-1-enyl, 1,4-cyclopentyl-2-ene-methyl,methyl-1,3-cyclohexyl, 1,2-cyclohexyl-methyl-, 1,3-cyclohexyl-methyl-,1S,3R-cyclohexyl-methyl-, 1R,3S-cyclohexyl-methyl,1,4-cyclohexyl-methyl-, 1,2-cyclohex-4-enyl, 1,3-phenyl-methyl and1-benzyl-methyl-;

R³ is selected from the group consisting of hydrogen, phenylamino,4-methylphenyl, 4-fluorophenyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl and4-trifluoromethylbenzyl;

Y is selected from the group consisting of -3-O—and -4-O—;

n is an integer selected from 0, 2 or 3;

R⁴ is selected from the group consisting of hydrogen, 4-morpholinyl,1-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl, 2-(1-methylpyrrolidinyl), 1-piperazinyl, 1-piperidinyl, di(methyl)aminoethyloxyethyl,N-methyl-N-benzyl-amino, di(methyl)amino and diethylamino;

R⁵ is selected from the group consisting of hydrogen, 2-methyl and6-methyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

In another preferred embodiment of the present invention are compoundsof the formula (I) wherein R¹, R² and X¹ are taken together (with theamine nitrogen) to form an optionally substituted, monocyclic or fusedbicyclic or tricyclic secondary amine ring structure selected from thegroup consisting of 1 -phenyl-1,2,3,4-tetrahydroisoquinolinyl,4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, 2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]naphthyl, isoindole- 1 ,3-dione,5-t-butyl-isoindole-1,3-dione, 5-fluoro-isoindole-1,3-dione,5-methyl-isoindole-1,3-dione, 5,6-dichloro-isoindole-1,3-dione,4,7-dichloro-isoindole-1,3-dione, 5-bromo-isoindole-1,3-dione,5-acetyloxy-isoindole-1,3-dione, benzo[e]isoindole-1,3-dione,8-fluorobenzo[e]isoindole-1,3-dione, 4,4-dimethyl-piperidine-2,6-dione,3-aza-bicyclo [3.1.0]hexane-2,6-dione and8-aza-spiro[4.5]decane-7,9-dione; and the pharmaceutically acceptablesalts, esters and pro-drug forms thereof.

In a particularly preferred embodiment R¹, R² and X¹ are taken together(with the amine nitrogen) to form1-phenyl-1,2,3,4-tetrahydroisquinolinyl, X² is C(O), A is 1,3-propyl, X³is C(O), R³ is 4-fluorobenzyl, Y is 3-O—, n is 2 and R⁴ is4-morpholinyl.

In another preferred embodiment R¹, R² and X¹ are taken together (withthe amine nitrogen) to form4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, X² is C(O), A is1,3-n-propyl, X³ is absent, R³ is 4-fluorophenyl, X⁴ is C(O), Y is 3-O—,n is 2 and R⁴ is 4-morpholinyl.

In still another preferred embodiment, R¹, R² and X¹are taken together(with the amine nitrogen) to form 2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]-naphthyl, X² is C(O), A is1,3-n-propyl, X³ is absent, R³ is 4-fluorophenyl, X⁴ is C(O), Y is 3-O—,n is 2 and R⁴ is 4-morpholinyl.

In a class of the invention are compounds of the formula (I) wherein R¹is selected from the group consisting of benzyl, 2-(phenyl)ethyl,3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl,3,5-dichlorobenzyl, 3-trifluoromethylbenzyl and 2-pyridyl-methyl;

R² is selected from the group consisting of t-butyl, 2-(phenyl)ethyl,trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl,2-(4-methoxyphenyl)ethyl, 2-(4-chlorophenyl)ethyl, diphenylmethyl,2-(2-pyridyl)ethyl, 2-(1-pyrrolidinyl)ethyl and 2-(2-thienyl)ethyl;

X¹, X², X³and X⁴ are independently absent or CO; such that one of X¹ orX² and one of X³ or X⁴ is CO;

A is selected from the group consisting of 1,2-ethyl, 1,3-propyl,2-methyl-1,3-propyl, 1,1, -dimethyl-(1,3-propyl),2-cyclopentyl-1,3-n-propyl, 1S,3R-cyclopentyl -methyl,1,3-cyclohexyl-methyl, 1 S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;

R³ is selected from the group consisting of phenylamino, 4-fluorophenyl,3-fluorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl,4-methoxybenzyl and 4-trifluoromethylbenzyl;

Y is selected from the group consisting of -3-O—and -4-O—;

n is an integer selected from 2 or 3;

R⁴ is selected from the group consisting of hydrogen, 4-morpholinyl,1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, di(methyl)amino anddi(ethyl)amino;

R⁵ is selected from the group consisting of hydrogen, 2-methyl and6-methyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

In another class of the invention are compounds of the formula (I)wherein

Ris selected from the group consisting of benzyl, 2-(phenyl)ethyl,3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl,3,5-dichlorobenzyl and 3-trifluoromethylbenzyl;

R² is selected from the group consisting of t-butyl, 2-(phenyl)ethyl,trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl, 2-(2-pyridyl)ethyland 2-(2-thienyl)ethyl;

X¹, X², X³ and X⁴ are independently absent or CO; such that one of X¹orX² and one of X³ or X⁴ is CO;

A is selected from the group consisting of 1,3-propyl,1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-,1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;

R³ is selected from the group consisting of phenylamino, 4-fluorophenyl,3-fluorobenzyl and 4-fluorobenzyl;

Y is -3-O—;

n is 2;

R⁴ is selected from the group consisting of hydrogen, 4-morpholinyl,1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino;

R⁵ is selected from the group consisting of hydrogen, 2-methyl and6-methyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

Particularly preferred are compounds of the formula (I) wherein

R¹ is selected from the group consisting of benzyl, 3-nitrobenzyl,3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl and3-trifluoromethylbenzyl;

R² is selected from the group consisting of t-butyl, 2-(phenyl)ethyl,trichloromethyl, 2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl;

X¹, X², X³ and X⁴ are independently absent or CO; such that one of X¹ orX² and one of X³ or X⁴ is CO;

A is selected from the group consisting of 1,3-propyl,1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-,1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;

R³ is selected from the group consisting of phenylamino, 4-fluorophenyl,3-fluorobenzyl and 4-fluorobenzyl;

Y is -3-O—;

n is 2;

R⁴ is selected from the group consisting of hydrogen, 4-morpholinyl,1-pyrrolidinyl and 1-piperidinyl;

R⁵ is selected from the group consisting of hydrogen and 2-methyl;

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

In still another particularly preferred embodiment of the presentinvention are compounds of the formula (I) wherein R¹ is 3-chlorobenzyl,R² is trichloromethyl, X¹ is CO, X² is absent, X³ is absent, X⁴ is CO, Ais 1S,3R-cyclohexyl -methyl-, R³ is 4-fluorophenyl, Y is -3-O—, n is 2,R⁴ is 1-piperidinyl, R⁵ is hydrogen and the pharmaceutically acceptablesalts, esters and pro-drug forms thereof.

In still another particularly preferred embodiment of the presentinvention are compounds of the formula (I) wherein R¹ is 3-chlorobenzyl,R² is trichloromethyl, X¹ is CO, X² is absent, X³ is absent, X⁴ is CO, Ais 1R,3S-cyclohexyl -methyl-, R³ is 4-fluorophenyl, Y is -3-O—, n is 2,R⁴ is 1-piperidinyl, R⁵ is hydrogen and the pharmaceutically acceptablesalts, esters and pro-drug forms thereof.

Listed in Tables 1-16 are specific compounds of the present invention.TABLE 1

ID # R¹ R² R³ 128 benzyl 2-(phenyl)ethyl 4-fluorobenzyl 1633-chlorobenzyl 2-(phenyl)ethyl 4-fluorobenzyl 164 benzyl 2-(phenyl)ethyl3-fluorobenzyl 165 benzyl 2-(phenyl)ethyl 2-fluorobenzyl 166 benzyl2-(phenyl)ethyl 4-methoxybenzyl 167 benzyl 2-(phenyl)ethyl4-trifluoromethylbenzyl 168 benzyl 2-(phenyl)ethyl 4-chlorobenzyl

TABLE 2

ID R¹ R² R³ Y n R⁴ R⁵ 129 benzyl 2-(phenyl)ethyl 4-fluoro 3-O 2 4- Hbenzyl morpholinyl 159 benzyl 3- 4-fluoro 3-O 2 4- H (phenyl)propylbenzyl morpholinyl 162 3-chloro 2-(phenyl)ethyl 4-fluoro 3-O 2 4- Hbenzyl benzyl morpholinyl 169 benzyl 2-(phenyl) 3-fluoro 3-O 2 4- Hethyl benzyl morpholinyl 170 benzyl 2-(phenyl) 2-fluoro 3-O 2 4- H ethylbenzyl morpholinyl 171 benzyl 2-(phenyl) 4-methoxy 3-O 2 4- H ethylbenzyl morpholinyl 172 benzyl 2-(phenyl) 4-trifluoro 3-O 2 4- H ethylmethyl morpholinyl benzyl 173 benzyl 2-(phenyl) 4-chloro 3-O 2 4- Hethyl benzyl morpholinyl 175 benzyl 2-(phenyl) 4-fluoro 3-O— 0 H H ethylbenzyl 176 benzyl 2-(phenyl) 4-fluoro 3-O 2 2-oxo- H ethyl benzylpyrrolidin-1- yl 177 benzyl 2-(phenyl) 4-fluoro 3-O 2 dimethyl H ethylbenzyl amino ethyloxy ethyl 178 benzyl 2-(phenyl) 4-fluoro 3-O 2 diethylH ethyl benzyl amino 179 benzyl 2-(phenyl) 4-fluoro 3-O 2 1-piperazinylH ethyl benzyl 180 benzyl 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl Hethyl benzyl 181 benzyl 2-(phenyl) 4-fluoro 3-O 2 dimethyl H ethylbenzyl amino 182 benzyl 2-(phenyl) 4-fluoro 3-O 2 1-piperidinyl H ethylbenzyl 187 benzyl 2-(phenyl) 4-fluoro 3-O 3 dimethyl H ethyl benzylamino 188 benzyl 2-(phenyl) 4-fluoro 3-O 3 1-piperidinyl H ethyl benzyl191 benzyl 2-(phenyl) 4-fluoro 4-O 2 1-pyrrolidinyl H ethyl benzyl 192benzyl 2-(phenyl) 4-fluoro 4-O 2 4- H ethyl benzyl morpholinyl 193benzyl 2-(phenyl) 4-fluoro 4-O 3 1-piperidinyl H ethyl benzyl 194 benzyl2-(phenyl) 4-fluoro 4-O 2 dimethyl H ethyl benzyl amino 195 benzyl2-(phenyl) 4-fluoro 4-O 2 diethyl H ethyl benzyl amino 196 benzyl2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl 2- ethyl benzyl methyl 1973-nitro 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl ethyl benzyl198 3-chloro 3-methoxy 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl benzylbenzyl 199 3,5- 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl H dichloroethyl benzyl benzyl 200 3-trifluoro 2-(phenyl) 4-fluoro 3-O 21-pyrrolidinyl H methyl ethyl benzyl benzyl 201 3-chloro 2-(2- 4-fluoro3-O 2 1-pyrrolidinyl H benzyl pyridyl)ethyl benzyl 202 3-chloro2-(4-chloro 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl phenyl)ethyl benzyl203 3-chloro 2-(1- 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl pyrrolidinyl)benzyl ethyl 204 3-chloro 2-(2-thienyl) 4-fluoro 3-O 2 1-pyrrolidinyl Hbenzyl ethyl benzyl 205 3-nitro 2-(phenyl) 4-fluoro 3-O 2 4- H benzylethyl benzyl morpholinyl 206 3-chloro 3-methoxy 4-fluoro 3-O 2 4- Hbenzyl benzyl benzyl morpholinyl 207 benzyl 2-(phenyl) 4-fluoro 3-O 21-pyrrolidinyl 6- ethyl benzyl methyl 215 2-(phenyl) 3-carboxy 4-fluoro3-O 2 1-pyrrolidinyl 2- ethyl benzyl benzyl methyl 234 benzyl 2-(phenyl)4-fluoro 3-O 2 4- 2- ethyl benzyl morpholinyl methyl

TABLE 3

ID R¹ R² A R³ 154 benzyl 2-(phenyl)ethyl 2-cyclopentyl-1,3-n-4-fluorobenzyl propyl 155 benzyl 2-(phenyl)ethyl cis-1,2-cyclohex-4-4-fluorobenzyl enyl 156 benzyl 2-(phenyl)ethyl 1,2-cylopentenyl H 160benzyl 2-(phenyl)ethyl 1,3-n-butyl 4-fluorobenzyl 189 benzyl2-(phenyl)ethyl 2-methyl-(1,3-propyl) 4-fluorobenzyl 190 benzyl2-(phenyl)ethyl 1,1-dimethyl-(1,3- 4-fluorobenzyl propyl)

TABLE 4

ID R¹ R² X⁴ R³ 5 benzyl 2-(phenyl)ethyl CO phenylamino 6 benzyl2-(phenyl)ethyl CO 4-methylphenyl 7 benzyl 2-(phenyl)ethyl CO4-fluorophenyl 12 benzyl ethyl SO₂ 4-methylphenyl 13 benzyl ethyl CO4-methylphenyl 14 benzyl ethyl CO 4-fluorophenyl 19 benzyl methyl COphenylamino 20 benzyl methyl SO₂ 4-methylphenyl 21 benzyl methyl CO4-methylphenyl 22 benzyl methyl CO 4-fluorophenyl 26 benzyl benzyl COphenylamino 27 benzyl benzyl SO₂ 4-methylphenyl 28 benzyl benzyl CO4-methylphenyl 29 benzyl benzyl CO 4-fluorophenyl 34 4-methylbenzylethyl CO phenylamino 35 4-methylbenzyl ethyl SO₂ 4-methylphenyl 364-methylbenzyl ethyl CO 4-methylphenyl 37 4-methylbenzyl ethyl CO4-fluorophenyl

TABLE 5

ID R¹ R² X⁴ R³ 1 benzyl 2-(phenyl)ethyl CO phenylamino 2 benzyl2-(phenyl)ethyl SO₂ 4-methylphenyl 3 benzyl 2-(phenyl)ethyl CO4-methylphenyl 4 benzyl 2-(phenyl)ethyl CO 4-fluorophenyl 8 benzyl ethylCO phenylamino 9 benzyl ethyl SO₂ 4-methylphenyl 10 benzyl ethyl CO4-methylphenyl 11 benzyl ethyl CO 4-fluorophenyl 15 benzyl methyl COphenylamino 16 benzyl methyl SO₂ 4-methylphenyl 17 benzyl methyl CO4-methylphenyl 18 benzyl methyl CO 4-fluorophenyl 23 benzyl benzyl COphenylamino 24 benzyl benzyl SO₂ 4-methylphenyl 25 benzyl benzyl CO4-methylphenyl 30 4-methylbenzyl ethyl CO phenylamino 31 4-methylbenzylethyl SO₂ 4-methylphenyl 32 4-methylbenzyl ethyl CO 4-methylphenyl 334-methylbenzyl ethyl CO 4-fluorophenyl 143 H diphenylmethyl CO4-fluorophenyl 144 benzyl 3-(phenyl)propyl CO 4-fluorophenyl 145 benzyl2,2-dimethylpropyl CO 4-fluorophenyl 146 benzyl 2-(4-methoxyphenyl) CO4-fluorophenyl ethyl 147 3-chlorobenzyl 2-(4-methoxyphenyl) CO4-fluorophenyl ethyl

TABLE 6

ID R¹ R² Stereo^(#) R³ R⁴ 232 3-chlorobenzyl t-butyl cis 4-fluorophenylN-methyl-N- racemate benzyl-amino 233 3-chlorobenzyl t-butyl cis4-fluorophenyl di(ethyl)amino racemate 235 3-chlorobenzyl t-butyl cis4-fluorophenyl 2-(1-methyl) racemate pyrrolidinyl 236 3-chlorobenzyltrichloro cis 4-fluorophenyl 2-(1-methyl) methyl racemate pyrrolidinyl237 3-chlorobenzyl t-butyl cis 4-fluorophenyl 1-piperidinyl racemate 2383-chlorobenzyl trichloro cis 4-fluorophenyl 1-piperidinyl methylracemate 239^(a) 3-chlorobenzyl trichloro 1S, 3R 4-fluorophenyl1-piperidinyl methyl 240^(b) 3-chlorobenzyl trichloro 1R, 3S4-fluorophenyl 1-piperidinyl methyl 264 hydrogen 3-carboxy- cis4-fluorophenyl 1-piperidinyl n-propyl racemate 265 hydrogen 3-carboxy-cis 4-fluorophenyl 1-piperidinyl 1,2,2- racemate trimethyl cyclopentyl266 hydrogen 3-methyl- cis 4-fluorophenyl 1-piperidinyl 3-carboxy-racemate n-butyl 267 hydrogen (1-carboxy cis 4-fluorophenyl1-piperidinyl methyl- racemate cyclopentyl)- methyl 268 hydrogen3-carboxy- cis 4-fluorophenyl 1-piperidinyl 2,2- racemate dimethyl-n-propyl^(#)The term “cis racemate” denotes a mixture of four possiblediastereomers, with the two cis diastereomers predominately present.

TABLE 7

ID R¹ X¹ R² R³ 40 benzyl CO phenylamino phenylamino 41 benzyl CO3-methoxyphenyl phenylamino 42 benzyl CO t-butyl phenylamino 43 benzylCO 2-(phenyl)ethyl phenylamino 44 benzyl CO 2-naphthyl phenylamino 45benzyl CO 3-nitrophenyl phenylamino 46 benzyl CO diphenylmethylphenylamino 47 3-chlorobenzyl CO trichloromethyl phenylamino 48 benzylCO 2-furyl phenylamino 49 3-chlorobenzyl CO 3,5-di-trifluoro phenylaminomethylphenyl 50 3-chlorobenzyl CO 4-biphenyl phenylamino 513-chlorobenzyl CO 3-methoxy phenylamino phenyl 52 3-chlorobenzyl COt-butyl phenylamino 53 3-chlorobenzyl CO 2-(phenyl)ethyl phenylamino 543-chlorobenzyl CO 2-naphthyl phenylamino 55 3-chlorobenzyl CO3-nitrophenyl phenylamino 56 3-chlorobenzyl CO diphenyl methylphenylamino 57 benzyl SO₂ 2-naphthyl phenylamino 58 3-fluorobenzyl COtrichloromethyl phenylamino 59 3,4-dichloro CO trichloromethylphenylamino benzyl 60 3,5-dichloro CO trichloromethyl phenylamino benzyl61 3-methoxybenzyl CO trichloromethyl phenylamino 62 3-trifluoromethylCO trichloromethyl phenylamino benzyl 63 4-chlorobenzyl COtrichloromethyl phenylamino 64 1-naphthyl- CO trichloromethylphenylamino methyl 65 3-nitrobenzyl CO trichloromethyl phenylamino 662,3-dichloro CO trichloromethyl phenylamino benzyl 67 benzyl COtrichloromethyl phenylamino 68 2-pyridyl-methyl CO trichloromethylphenylamino 69 H CO phenynamino phenylamino 70 H CO 2-furyl phenylamino71 H SO₂ 2-naphthyl phenylamino 72 H CO trichloromethyl phenylamino 73 HCO trifluoromethyl phenylamino 74 H CO 3,5-di-trifluoro phenylaminomethylphenyl 75 H CO 4-biphenyl phenylamino 76 H CO 3-methoxyphenylphenylamino 77 H CO 1-butyl phenylamino 78 H CO 2-(phenyl)ethylphenylamino 79 H CO 2-naphthyl phenylamino 80 H CO 3-nitrophenylphenylamino 81 H CO diphenylmethyl phenylamino 82 benzyl CO3,5-di(trifluoro phenylamino methyl)phenyl 83 benzyl CO 4-biphenylphenylamino 86 3-chlorobenzyl CO 3-hydroxyphenyl phenylamino 902-pyridyl-methyl CO trichloromethyl 4-fluorophenyl 91 H COtrichloromethyl 4-fluorophenyl 92 2,3-dichloro CO trichloromethyl4-fluorophenyl benzyl 93 3-nitrobenzyl CO trichloromethyl 4-fluorophenyl94 1-naphthyl- CO trichloromethyl 4-fluorophenyl methyl 954-chlorobenzyl CO trichloromethyl 4-fluorophenyl 96 3-trifluoromethyl COtrichloromethyl 4-fluorophenyl benzyl 97 3-methoxybenzyl COtrichloromethyl 4-fluorophenyl 98 3,5-dichloro CO trichloromethyl4-fluorophenyl benzyl 99 3,4-dichloro CO trichloromethyl 4-fluorophenylbenzyl 100 3-fluorobenzyl CO trichloromethyl 4-fluorophenyl 1013-chlorobenzyl CO diphenylmethyl 4-fluorophenyl 102 3-chlorobenzyl CO3-nitrophenyl 4-fluorophenyl 103 3-chlorobenzyl CO 2-naphthyl4-fluorophenyl 104 3-chlorobenzyl CO 2-(phenyl)ethyl 4-fluorophenyl 1053-chlorobenzyl CO t-butyl 4-fluorophenyl 106 3-chlorobenzyl CO3-methoxyphenyl 4-fluorophenyl 107 3-chlorobenzyl CO 3,5-di-trifluoro4-fluorophenyl methylphenyl 108 3-chlorobenzyl CO trifluoromethyl4-fluorophenyl 109 3-chlorobenzyl CO 4-biphenyl 4-fluorophenyl 1103-chlorobenzyl CO 3,3,3-trifluoro 4-fluorophenyl propan-2-onyl 1113-chlorobenzyl CO trichloromethyl 4-fluorophenyl 112 benzyl COdiphenylmethyl 4-fluorophenyl 113 benzyl CO 3-nitrophenyl 4-fluorophenyl114 benzyl CO 2-naphthyl 4-fluorophenyl 115 benzyl CO 2-(phenyl)ethyl4-fluorophenyl 116 benzyl CO t-butyl 4-fluorophenyl 117 benzyl CO3-methoxyphenyl 4-fluorophenyl 118 benzyl CO 4-biphenyl 4-fluorophenyl119 benzyl CO 3,5-ditrifluoro 4-fluorophenyl methylphenyl 120 benzyl COtrifluoromethyl 4-fluorophenyl 121 benzyl CO 3,3,3-trifluoro4-fluorophenyl propan-2-onyl 122 benzyl CO trichloromethyl4-fluorophenyl 123 benzyl SO₂ 2-naphthyl 4-fluorophenyl 124 benzyl CO2-furyl 4-fluorophenyl 125 benzyl CO phenylamino 4-fluorophenyl 2413-chlorobenzyl CO 3-methoxybenzyl 4-fluorophenyl 242 3-chlorobenzyl CO2- 4-fluorophenyl cyclopentylethyl 243 3-chlorobenzyl CO 4-methoxybenzyl4-fluorophenyl 244 3-chlorobenzyl CO Benzyl 4-fluorophenyl 2453-chlorobenzyl CO 3,4- 4-fluorophenyl dimethoxybenzyl 246 3-chlorobenzylCO t-butylmethyl 4-fluorophenyl 247 3-chlorobenzyl CO 1(1-phenyl)4-fluorophenyl propyl 248 3-chlorobenzyl CO 2-thienylmethyl4-fluorophenyl 249 3-chlorobenzyl CO 4-fluorobenzyl 4-fluorophenyl

TABLE 8

ID R¹ R² R³ 158 H trichloromethyl 4-fluorophenyl 161 3-chlorobenzylt-butyl 4-fluorophenyl 157 benzyl trifluoromethyl 4-fluorophenyl

TABLE 9

ID R¹ R² Stereo^(#) R³ R⁵ 208 3-nitrobenzyl trichloromethyl 1S, 3R4-fluorophenyl CH₃ 209 3-chlorobenzyl trichloromethyl 1S, 3R4-fluorophenyl CH₃ 210 benzyl trichloromethyl 1S, 3R 4-fluorophenyl CH₃223 3-chlorobenzyl trichloromethyl cis phenylamino H racemate 224 benzyltrichloromethyl cis phenylamino H racemate 225 benzyl t-butyl cisphenylamino H racemate 226 3-chlorobenzyl t-butyl cis 4-fluorophenyl Hracemate 227 3,4-dichlorobenzyl t-butyl cis 4-fluorophenyl H racemate228 3,4-difluorobenzyl 1-butyl cis 4-fluorophenyl H racemate 229 benzylt-butyl 1S, 3R 4-fluorophenyl H 230 benzyl t-butyl 1R, 3S 4-fluorophenylH 211 3-nitrobenzyl trichloromethyl cis 4-fluorophenyl H racemate 2123-chlorobenzyl trichloromethyl cis 4-fluorophenyl H racemate 213 benzyltrichloromethyl cis 4-fluorophenyl H racemate 214 benzyl t-butyl cis4-fluorophenyl H racemate^(#)The term “cis racemate” denotes a mixture of four possiblediastereomers, with the two cis diastereomers predominately present.

TABLE 10

ID R¹ R² R³ 174 2-pyridylmethyl trichloromethyl 4-fluorophenyl 183benzyl benzyl phenylamino 184 3-chlorobenzyl 3-methoxyphenyl phenylamino185 3-chlorobenzyl 2-furyl phenylamino 186 3-nitrobenzyl 3-methoxyphenylphenylamino

TABLE 11

ID R¹ R² Stereo R³ 216 benzyl t-butyl 1S, 3R 4-fluorophenyl 2173-chlorobenzyl 1-butyl 1S, 3R 4-fluorophenyl 218 benzyl trichioromethyl1S, 3R 4-fluorophenyl 219 3-nitrobenzyl trichioromethyl 1S, 3R4-fluorophenyl 220 3,4-difluorobenzyl t-butyl 1S, 3R 4-fluorophenyl 231benzyl trichloromethyl 1R, 3S 4-fluorophenyl

TABLE 12

ID R¹ X¹ R² 130 H CO 2-(phenyl)ethyl 131 H CO trichioromethyl 132 H CO4-biphenyl 133 H CO diphenylmethyl 134 H CO 3-methoxybenzyl 135 H SO₂4-biphenyl 151 benzyl CO trichioromethyl 152 benzyl CO 2-(phenyl)ethyl

TABLE 13

ID R¹ R² 136 benzyl 2-(phenyl)ethyl 137 H diphenylmethyl 138 H2-(phenyl)ethyl 139 benzyl 3-(phenyl)propyl 140 benzyl2,2-dimethylpropyl 141 3-chlorobenzyl 2,2-dimethylpropyl

TABLE 14

R¹, R² and X¹ Taken Together (with the ID amine nitrogen) A X³ X⁴ R³ 1421-phenyl-1,2,3,4- 1,3-phenyl- absent CO 4-fluoro tetrahydroisoquinolin-methyl phenyl 2-yl 148 1-phenyl-1,2,3,4- 1,3-n-propyl absent CO 4-fluorotetrahydroisoquinolin- phenyl 2-yl 149 4-[(4- 1,3-n-propyl absent CO4-fluoro chlorophenyl)phenyl- phenyl methyl]-piperazin- 1-yl 1502-[1-benzyl-6- 1,3-n-propyl absent CO 4-fluoro methoxy-1,2,3,4-tetra-phenyl hydro]-naphthyl 153 1-phenyl-1,2,3,4- 1,3-n-propyl CO absent4-fluoro tetrahydroisoquinolinyl benzyl

TABLE 15

ID R¹ R² A R³ R⁴ 39 3-chloro trichloro methyl-1,3- phenyl 4-morpholinylbenzyl methyl cyclopentyl amino 221 benzyl t-butyl 1,4-cyclopentyl-4-fluoro 1-pyrrolidinyl 2-ene-methyl phenyl

TABLE 16

R¹, R² and X¹ Taken Together (with the ID amine nitrogen) 2505-t-butyl-isoindole-1,3-dione 251 5-fluoro-isoindole-1,3-dione 252benzo[e]isoindole-1,3-dione 253 5-methyl-isoindole-1,3-dione 2548-aza-spiro[4.5]decane-7,9-dione 255 5,6-dichloro-isoindole-1,3-dione256 5-methyl-isoindole-1,3-dione 257 isoindole-1,3-dione 2584,4-dimethyl-piperidine-2,6-dione 259 5-bromo-isoindole-1,3-dione 2605-acetyloxy-isoindole-1,3-dione 261 8-fluoro-benzo[e]isoindole-1,3-dione262 3-aza-bicyclo[3.1.0]hexane-2,4-dione 2634,7-dichloro-isoindole-1,3-dione

Particularly preferred intermediates in the preparation of compounds offormula (I) are listed in Table 17 below. TABLE 17

ID # R¹ R² R³ R⁴ 84 benzyl H phenylamino 4-morpholino 85 3-chlorobenzylH phenylamino 4-morpholino 87 3,5-dichlorobenzyl H phenylamino4-morpholino 88 1 -naphthylmethyl H phenylamino 4-morpholino 894-(1-hydroxy)-pyridyl H phenylamino 4-morpholino 222 benzyl benzyl4-fluorophenyl 1-pyrrolidinyl

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceucally acceptable carrier and any of the compounds describedabove. Illustrating the invention is a pharmaceutical composition madeby mixing any of the compounds described above and a pharmaceuticallyacceptable carrier. A further illustration of the invention is a processfor making a pharmaceutical composition comprising mixing any of thecompounds described above and a pharmaceutically acceptable carrier.

Included in the invention is the use of any of the compounds describedabove for the preparation of a medicament for treating a disordermediated by the motilin receptor, in a subject in need thereof.

Also included in the invention is the use of any of the compoundsdescribed above for the preparation of a medicament for treating acondition selected from gastrointestinal reflux disorders, eatingdisorders leading to obesity and irritable bowel syndrome in a subjectin need thereof.

Exemplifying the invention are methods of treating a disorder mediatedby the motilin receptor, in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above.

An example of the invention is a method for treating a conditionselected from gastrointestinal reflux disorders, eating disordersleading to obesity and irritable bowel syndrome in a subject in needthereof, comprising administering to the subject an effective amount ofany of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed above in the preparation of a medicament for: (a) treatinggastrointestinal reflux disorders, (b) treating irritable bowelsyndrome, (c) treating eating disorders leading to obesity, in a subjectin need thereof.

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkyl”, unless otherwise specified, refers to straight orbranched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms,preferably 1 to 8 carbon atoms. The expression “lower alkyl” refers tostraight or branched chain unsubstituted alkyl groups of 1 to 6 carbonatoms. For example, alkyl radicals include, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,3-methylbutyl, 2-pentyl, 2-methylpropyl, 2-methylbutyl,3,3-dimethylpropyl, neo-pentyl, n-hexyl, 2-hexyl and 2-methylpentyl.Similarly, the term “alkenyl”, unless otherwise specified, refers tostraight or branched chain alkene groups of 2 to 10 carbon atoms. Theterm “lower alkenyl” refers to straight or branched chain alkene groupsof 2 to 6 carbon atoms.

The term “substituted alkyl”, unless otherwise specified, refers to analkyl group substituted by, for example, one to four substituents, suchas, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy,cycloalkyoxy, heterocyclyloxy, oxo, alkanoyl, aryloxy, alkanoyloxy,amino, alkylamino, arylamino, aralkylamino, cycloalkylamino,heterocycloamino, disubstituted amines in which the amino substituentsare independently selected from alkyl, aryl or aralkyl, alkanoylamine,aroylamino, aralkanoylamino, substituted alkanoylamino, substitutedarylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio,aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono,aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido(e.g. SO₂NH₂), substituted sulfonamido, nitro, cyano, carboxy, carbamyl(e.g. CONH₂) substituted carbamyl (e.g.CONH alkyl, CONH aryl, CONHaralkyl or cases where there are two substituents on the nitrogenselected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substitutedaryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl,thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term “cycloalkyl”, unless otherwise specified, refers to saturatedunsubstituted cyclic hydrocarbon ring systems, preferably containing 1to 3 rings and 3 to 8 carbon atoms per ring. For example, cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like. Similarly, the term “cycloalkenyl” refers topartially unsaturated, unsubstituted cyclic hydrocarbon groups of 3 to20 carbon atoms, preferably 3 to 8 carbon atoms. Suitable examples ofcycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl,cyclooctyl, cyclodecyl, cyclododecyl, adamantyl, and the like.

The term “alkoxy”, unless otherwise specified, refers to oxygen etherradical of the above described straight or branched chain alkyl groups.The expression “lower alkoxy” refers to unsubstituted alkoxy groups of 1to 6 carbon atoms. Suitable examples of alkoxy groups include methoxy,ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

The term “aryl”, unless otherwise specified, refers to monocyclic orbicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in thering portion, such as phenyl, naphthyl, biphenyl and diphenyl, each ofwhich may be optionally substituted.

The term “aralkyl”, unless otherwise specified, refers to an aryl groupbonded directly through an alkyl group, such as benzyl, 2-(phenyl)ethyl,3-(phenyl)propyl, naphthyl-methyl and the like.

The term “substituted aryl” refers to an aryl group substituted by, forexample, one to five substituents such as alkyl; substituted alkyl,halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy,heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino,cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol,alkylthio, cycloalkylthio, heterocyclothio, ureido nitro, cyano,carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono,arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like.

The term “diarylalkyl”, unless otherwise specified, refers to an alkylgroup substituted with two independently selected aryl groups. Suitableexamples include diphenylmethyl, 1,1-diphenylethyl, and the like.

The term “heteroatom” shall include oxygen, sulfur and nitrogen.

The terms “heterocyclyl”, “heterocyclic” and “heterocyclo”, unlessotherwise specified, refer to a saturated, unsaturated, partiallyunsaturated, aromatic, partially aromatic or non-aromatic cyclic group.Such a group, for example, can be a 4 to 7 membered monocyclic or a 7 to11 bicyclic ring system which contains at least one heteroatom in atleast one carbon atom containing ring. Each ring of the heterocyclicgroup containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selectedfrom nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogenand sulfur heteroatoms may also optionally be oxidized and where thenitrogen heteroatoms may also optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl,azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane,tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl, orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzoth ienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isoch romanyl, isoindolinyl, naphthyridinyl,phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl,tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and thelike.

The term “monocyclic or fused bicyclic or tricyclic secondary amine ringstructure” shall mean any 4 to 8 monocyclic or 7 to 1 1 fused bicyclicor 13 to 14 tricyclic ring structure; wherein the ring structure issaturated, partially unsaturated or benzo-fuzed; wherein the ringstructure contains at least one nitrogen atom through which the ringstructure is bound directly to the other portions of the compound; andwherein the ring structure may optionally containing one to threeadditional heteroatoms selected from nitrogen, oxygen or sulfur.

Suitable examples include 1,2,3,4-tetrahydroisoquinolinyl,1-piperazinyl, 1,2,3,4-tetrahyd ronaphthyl, isoindolyl,benzo[e]isoindolyl, 8-aza-spiro[4.5]decane, 3-aza-bicyclo[3.1.o]hexane,and the like.

The monocylic, bicyclic or tricyclic secondary amine ring structure mayoptionally be substituted with one to five substituents independentlyselected from alkyl, substituted alkyl, halo, trifluoromethoxy,trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy,alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino,heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio,cycloalkylthio, heterocyclothio, ureido nitro, cyano, oxo, carboxy,carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,alkysulfonyl, sulfonamido, aryloxy, aryl, aralkyl, heterocyclyl, and thelike.

The term “tri-halomethyl” refers to trichloromethyl, trifluoromethyl,tribromomethyl and triiodomethyl.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

As used herein, the term “cis racemate” indicates a mixture of fourpossible diastereomers, more particularly, two cis diastereomers and twotrans diastereomers, with the two cis diastereomers present in a amountequal to greater than about 75%, preferably in an amount greater thanabout 90%, more preferably in an amount greater than about 95%.

When a particular group is “substituted” (e.g., aryl, heteroaryl,heterocyclyl), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents. Where the grouphas a plurality of moieties, such as “alkylamino” or“heterocyclyl-alkyl” the substitution may be on any or all of themoieties independently, e.g. in the case of “alkylamino” thesubstitution may be on the alkyl or amino moiety, or both.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Suitable protecting groups as referred to within this specificationinclude the standard hydroxy and amino protecting groups, as applicable.The terms “hydroxy protecting group” and “amino protecting group” asused herein mean any of the known protecting groups used in the art oforganic synthesis, for example as described in Protective Groups inOrganic Synthesis, 2nd Ed., T.W. Greene and P. G. M. Wuts, John Wiley &Sons, New York, 1991, hereby incorporated by reference.

Examples of hydroxy-protecting groups P, include, but are not limitedto, methyl, benzyl, tetrahydropyranyl, tri(C₁-C₆)alkylsilyl such ast-butyldimethylsilyl, t-butyl, 2-methoxyethoxymethyl (MEM),4-dimethylcarbamoylbenzyl and O-phenoxyacetyl ethers. Thehydroxy-protecting group selected is preferably one that is easilyremovable in the reaction process.

Examples of suitable amino protecting groups include, but are notlimited to, acetyl (Ac), benzoyl (Bz), trifluoroacetyl (Tfa),toluenesulfonyl (Tos), benzyl (Bn), triphenylmethyl (Trt),o-nitrophenyl-sulfenyl (Nps), benzyloxycarbonyl (Cbz or Z),t-butoxycarbonyl (Boc), allyloxycarbonyl (alloc),9-fluorenylmethyloxycarbonyl (Fmoc), 2-bromo-benzyloxycarbonyl (2-Br-Z),2-chloro-benzyloxycarbonyl (2-CI-Z), t-butyl-dimethylsilyloxycarbonyl,[2-(3,5-dimethoxyphenyl) -propyl-2-oxycarbonyl] (Ddz),2,2,2-trichloroethyloxycarbonyl (Troc), biphenylylisopropyloxycarbonyl(Bpoc), and o-nitrobenzyloxycarbonyl.

Throughout this specification, certain abbreviations are employed havingthe following meanings, unless specifically indicated otherwise.

-   -   AcOH=Acetic Acid    -   ADDP=1,1′-(azodicarbonyl)dipiperidine    -   BSA=Bovine Serum Albumin    -   DCM=Dichloromethane    -   DEAD=Diethyl azodicarboxylate    -   DIEA Diisopropylethylamine    -   DMAP=Di(methyl)aminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=Dimethylsulfoxide    -   EA=Ethyl acetate    -   EDCI=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   EDTA=Ethylenediamine tetraacetic acid    -   EGTA=Ethylene glycol-bis(β-aminoethyl        ether)-N,N,N′,N′-tetraacetic acid    -   Et₂O=Diethyl ether    -   EtOAc=Ethyl acetate    -   EtOH=Ethanol    -   Et₃N=Triethylamine    -   HEPES=N-(2-hydroxyethyl)piperazine-N-ethanesulfonic acid    -   LAH=Lithium Aluminum Hydride    -   MeOH=Methanol    -   Mel=Methyl Iodide    -   Oms=Mesylate    -   Otos=Tosylate    -   Phe=Phenyl    -   Pt=Protecting Group    -   PyBOP=Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium        hexafluorophosphate    -   TBAF=Tetrabutylammonium fluoride    -   TEA=Triethylamine    -   TFA=Trifluoroacetic Acid    -   THF=Tetrahydrofuran    -   Tris-HCI=Tris[hydroxymethyl]aminomethyl hydrochloride

The synthesis of substituted N-benzyl-m-anisidines, compounds of formula(II), intermediates used in the synthetic route for select compounds ofthe invention, are known in the art.

Routes for synthesis of substituted N-benzyl-m-anisidines includealkylation (Hoerlein; Chem. Ber.; 87; 1954; 463, 467, 468), reductiveamination (Nussbaumer, P.; et. al.; J Med Chem.; 37; 24; 1994;4079-4084) and reduction of the corresponding N-benzoyl-m-anisidine(Pratt; McGovern; J. Org. Chem.; 29; 1964; 1540, 1542). Additionally,N-benzyl-N-phenyl-malonamic acid methyl ester, a compound of formula(III) below, is a known compound, a variant of one of the intermediateselucidated in the synthesis that follows (Wee, A.; Tetrahedron, 50; 3;1994; 609-626).

Routes to the synthesis of 4-phenyl-1,2,3,4-tetrahydroisoquinolines arealso known in the literature (Maryanoff, B., et. al., J. Org. Chem., 46,1981, 355-360; Schwan, T. et. al., J. Heterocycl. Chem., 1974, 11, 807;and references therein).

Schemes 1-8 below depict synthesis routes for producing compounds of theformula (I).

Compounds of formula (I) wherein X² and X³ are each carbonyl, X¹ and X⁴are each absent and R³ is —CH₂—R⁶, may be produced according to theprocess outlined in Scheme 1. The process of Scheme 1 is particularlypreferred for preparation of compounds of formula (I) wherein A isincorporated into the molecule via reaction with a suitably selectedunsymmetrically substituted anhydride; wherein A is a substituted alkyl;and wherein it is desired to have the substituent closer to the R¹X¹R²Nportion of the compound of formula (I).

More specifically, a protected aniline derivative of formula (IV),wherein Pt represents a protecting group, a known compound or compoundprepared by known methods, is reacted with a suitably substitutedaldehyde of the formula (V), wherein R^(3A) is selected from hydrogen,aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclo-alkyl,tri-halomethyl, alkylamino, dialkylamino, alkylaminoalkyl, arylamino,diarylamino or lower alkyl; in the presence of a reducing agent such assodium cyanoborohydride, sodium triacetoxyborohydride, and the like,under dehydrating conditions, for example, in an acid alcohol solutionsuch as acidic methanol or in a solution of titanium tetraisopropoxidein DCM, to produce the corresponding secondary aniline derivative offormula (VI).

The secondary aniline derivative of formula (VI) is coupled with asuitably selected, protected dicarboxylic acid of formula (VII), whereinPt′ is a protecting group or with an anhydride of the desiredsubstituent A, to produce the corresponding acid-amide of formula(VIII).

When the secondary aniline derivative of formula (VI) is coupled with acyclic anhydride of the desired substituent A, such as glutaricanhydride and the like, the anhydride ring is subjected to ring opening,preferably at a temperature between about room temperature and about110° C., in an organic solvent such as chloroform, toluene, and thelike.

When the secondary aniline derivative of formula (VI) is coupled with aprotected dicarboxylic acid of formula (VII), the protecting group isthen removed by hydrolysis, using an inorganic base such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like, in analcohol or in an organic solvent/water mixture such as methanol,ethanol, THF/water, preferably lithium hydroxide in THF/water.

The acid-amide compound of formula (VIII) is activated using a knowncoupling agent, such as EDCI and the like, and coupled with a suitablysubstituted amine of formula (IX), in an organic base such as TEA, DIEA,and the like, in the presence of an organic solvent such as THF, DMF,DCM and the like, to produce the corresponding diamide of formula (X).

Alternatively, the acid-amine compound of formula (VIII) may beconverted to the corresponding acid chloride with a reagent such thionylchloride, oxalyl chloride, and the like, and then coupled to thesubstituted amine of formula (IX) to produce the diamide of formula (X).

The compound of formula (X) is deprotected by known methods [forexample, when the protecting group is methyl ether, the methyl group isremoved with boron tribromide in dichloromethane at −78° C.; when theprotecting group is t-butyldimethylsilylether, the silyl group isremoved with tetrabutylammonium fluoride in THF] to produce thecorresponding compound of formula (XI).

The compound of formula (XI) is reacted with a suitably substitutedcompound of formula (XII), wherein W represents a leaving group such ashalogen, OMS, OTos, and the like, in the presence of a base such assodium hydride, potassium carbonate, and the like, in an organic solventsuch as DMF, THF, and the like, to produce the corresponding compound offormula (Ia). Alternatively, when W is OH, the compound of formula (XI)may be reacted directly, under Mitsunobu conditions, to a suitablysubstituted compound of formula (XII).

Compounds of formula (I) wherein X² and X³ are each carbonyl, X¹ and X⁴are each absent and R³ is —CH₂—R⁶ may alternatively be preparedaccording to the process outlined in Scheme 2.

Accordingly, a suitably substituted nitrobenzene of formula (XIII), acompound prepared by known methods, is reacted with a suitablysubstituted compound of formula (XII), wherein W represents a leavinggroup such as halogen, OMS, OTos, and the like, in the presence of abase such as sodium hydride, triethylamine, and the like, in an organicsolvent such as DMF, THF, and the like, to produce the correspondingcompound of formula (XIV).

The nitro group on the compound of formula (XIV) is reduced by knownmethods, for example by hydrogenation over palladium on carbon in ethylacetate, to produce the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably substitutedaldehyde of formula (V), wherein R^(3A) is as previously defined, in thepresence of a reducing agent such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like, under dehydrating conditions, forexample, in an acid alcohol solution such as acidic methanol or in asolution of titanium tetraisopropoxide in DCM, to produce thecorresponding compound of formula (XVI).

The compound of formula (XVI) is reacted with a suitably selectedanhydride of the desired A substituent, optionally in an organic solventsuch as THF, DMF, DCM, and the like, to produce the correspondingcompound of formula (XVII). When reacting with a cyclic anhydride of thedesired substituent A, such as glutaric anhydride and the like, theanhydride ring is subjected to ring opening, preferably at a temperaturebetween about room temperature and about 110° C., in an organic solventsuch as chloroform, toluene, and the like.

The compound of formula (XVII) is coupled with a suitably substitutedamine of formula (IX), in the presence of a coupling agent, such asPyBOP, and the like, in an organic solvent such as THF, DMF, DCM, andthe like, to produce the corresponding compound of formula (Ib).

Compounds of formula (I) wherein X² and X³ are each carbonyl, X¹ and X⁴are each absent and R³ is —CH₂—R⁶, may alternatively be preparedaccording to the process outlined in Scheme 3. This process isparticularly preferred for preparation of compounds of formula (I)wherein A is incorporated into the molecule via reaction with a suitablyselected, unsymmetrically substituted anhydride; wherein A is asubstituted alkyl; and wherein it is desired to have the substituentdistal to the R¹X¹R²N portion of the compound of formula (I).

More specifically, a suitably substituted amine of formula (IX) isreacted with a suitably selected anhydride of the desired A substituent,in an organic solvent such as THF, DMF, DCM, and the like, to producethe corresponding compound of formula (XVIII). When the compound offormula (IX) is coupled with a cyclic anhydride of the desired Asubstituent, such as glutaric anhydride and the like, the anhydride ringis subjected to ring opening, preferably at a temperature between aboutroom temperature and about 110° C., in an organic solvent such aschloroform, toluene, and the like.

The compound of formula (XVIII) is coupled with a suitably substitutedcompound of formula (XVI), prepared as in Scheme 2 above, in an organicsolvent such as THF, DMF, DCM and the like, after conversion of thecompound of formula (XVIII) to the corresponding acid chloride using areagent such as thionyl chloride, oxalyl chloride, and the like, toproduce the corresponding compound of formula (Ib).

Alternatively, the compound of formula (XVIII) may be coupled directlywith a suitably substituted compound of formula (XVI), optionally in thepresence of a coupling agent such as PyBrop, and the like, in an organicsolvent such as THF, DMF, DCM, and the like.

Compounds of formula (I) wherein X¹and X³ are each absent, X² iscarbonyl, and X⁴ is carbonyl or sulfonyl, may be prepared according tothe process outlined in Scheme 4.

More specifically, an anhydride of the desired substituent A is reactedwith a suitably substituted compound of formula (XIV), prepared asoutlined in scheme 2, in an organic solvent such as THF, DMF, DCM andthe like, to produce the corresponding compound of formula (XIX).

The compound of formula (XIX) is coupled with a suitably substitutedamine of formula (IX), in the presence of a coupling agent, such asPyBOP, and the like, in an organic solvent such as THF, DMF, DCM and thelike, to produce the corresponding compound of formula (XX).

The compound of formula (XX) is selectively reduced, by known methods,for example, by reacting with sodium cyanoborohydride in AcOH(Tetrahedron Letters, 10, 763-66, 1976), to produce the correspondingcompound of formula (XXI).

The compound of formula (XXI) is reacted with an appropriately selectedand suitably substituted isocyanate of formula (XXII), wherein R^(3A) isa previously defined, or a sulfonyl chloride of formula (XXIII) or acarbonyl chloride of formula (XXIV), in an organic solvent such as THF,DMF, DCM and the like, to produce the corresponding compound of formula(Ic).

Compounds of formula (I) wherein X¹ and X⁴ are each carbonyl or sulfonyland X² and X³ are each absent, may be prepared according to the processoutlined in Scheme 5. This process is particularly preferred for thepreparation of compounds of formula (I) wherein A is-cyclohexyl-methyl-, -cyclopentyl-methyl and -cyclopentenyl-methyl-.

Accordingly, a trityl-protected compound of formula (XXV), wherein A¹ iscycloalkyl, cycloalkenyl, alkyl-cycloalkyl, aryl or alkyl-aryl, a knowncompound or compound prepared by known methods, [for example by themethod disclosed in K. Barlos, D. Theodoropoulos, and D. Papaioannou inJ. Org. Chem. 1982, 47, 1324-1326], is coupled to a suitably substitutedcompound of formula (XIV), prepared according to Scheme 2 above, using acoupling agent such as PyBOP, and the like, to produce the correspondingcompound of formula (XXVI).

The compound of formula (XXVI) is subjected to reduction of the carbonylgroup using known reducing agents, for example borane dimethylsulfide atreflux, lithium aluminum hydride in THF, and the like, to produce thecorresponding compound of formula (XXVII).

The compound of formula (XXVII) is reacted with an appropriatelyselected and suitably substituted isocyanate of formula (XXII), whereinR^(3A) is as previously defined, sulfonyl chloride of formula (XXIII) orcarbonyl chloride of formula (XXIV), in an organic solvent such as DCM,toluene, chloroform, and the like, to produce the corresponding compoundof formula (XXVIII).

The compound of formula (XXVIII) is deprotected by removal of the tritylprotecting group, using a solution of trifluoroacetic acid indichloromethane, to produce the corresponding compound of formula(XXIX).

The compound of formula (XXIX) is reacted with a suitably substitutedaldehyde of formula (XXX), wherein R^(1A) is selected from the groupconsisting of hydrogen, aryl, aralkyl, heterocyclyl, diarylalkyl,heterocyclyl-alkyl, and lower alkyl; wherein the alkyl, aryl,heterocyclyl or amino group may be substituted with one or moresubstituents independently selected from halogen, hydroxy, nitro,carboxy, cyano, amino, dialkylamino, lower alkoxy, lower alkyl,tri-halomethyl, alkylamino, carboxy or alkoxycarbonyl; by known methods,[for example by reductive amination or by the method of R. Mattson, et.al., in J. Org. Chem. 1990, 55, 2552-2554 using stepwise addition oftitanium tetraisopropoxide neat or in a dichloromethane, followed byaddition of methanol and sodiumcyanoborohydride], to produce thecorresponding compound of formula (XXXI).

The compound of formula (XXXI) is reacted with an appropriately selectedand suitably substituted isocyanate of formula (XXXII), wherein R^(2A)is selected from aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl,diarylalkyl, tri-halomethyl, arylamino or lower alkyl, or a sulfonylchloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV),or an anhydride of formula (XXXXVII) in an organic solvent such as DCM,toluene, and the like, to produce the corresponding compound of formula(Id). When the compound of formula (XXXI) is reacted with a sulfonylchloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV),the reaction is carried out with further addition of an organic basesuch as TEA, DIPEA, and the like.

Compounds of formula (I) wherein A is a substituted alkyl mayalternatively be prepared according to the process outlined in Scheme 6.

More specifically, a suitably substituted compound of formula (XVI),prepared as described in Scheme 2 above, is coupled with anappropriately selected, Fmoc protected compound of formula (XXXV), in anorganic solvent such as DCM, DMF, and the like, to produce thecorresponding compound of formula (XXXVI).

The compound of formula (XXXVI) is deprotected by removal of the Fmocprotecting group by known methods [for example by treating withpiperidine in DMF], to produce the corresponding compound of formula(XXXVII).

The compound of formula (XXXVII) is reacted with a suitably substitutedaldehyde of formula (XXX), wherein R^(1A) is as previously defined, inthe presence of a reducing agent such as sodium cyanoborohydride, andthe like, under dehydrating conditions, for example in an acid alcoholsolution such as acidic methanol or in a solution of titaniumtetraisopropoxide in DCM, followed by addition of methanol and sodiumcyanoborohydride, to produce the corresponding compound of formula(XXXVIII).

The compound of formula (XXXVIII) is coupled with an appropriatelyselected and suitably substituted isocyanate of formula (XXXII), whereinR^(2A) is as previously defined, sulfonyl chloride of formula (XXXIII)or carbonyl chloride of formula (XXXIV), in an organic solvent such asDCM, and the like, in the presence of an organic base such as TEA, DIEA,and the like, to produce the corresponding compound of formula (Ie).

Optionally, the compound of formula (XXXVIII) may be further reactedwith a second equivalent of the compound of formula (XXX) to yield aderivative of the compound of formula (XXXVIII), wherein the leftmostamine nitrogen is di-substituted with the —CH₂—R¹A group, wherein R^(1A)is as previously defined.

Compounds of formula (I), particularly those wherein X¹ and X³ are eachabsent, X² is carbonyl and X⁴ is carbonyl or sulfonyl may be preparedaccording to the process outlined in Scheme 7. This process isparticularly preferred for preparation of compounds of formula (I)wherein A is contains a non-hydrogen substituent alpha to the right-handmost amine nitrogen.

Accordingly, a suitably substituted compound of formula (XV), preparedas in Scheme 2 above, is alkylated with an appropriately selectedcompound of formula (XXXIX), ins an organic solvent such as DCM,chloroform, and the like, to produce the corresponding compound offormula (XXXX).

The compound of formula (XXXX) is coupled with an appropriately selectedand suitably substituted isocyanate of formula (XXII), wherein R^(3A) isas previously defined, sulfonyl chloride of formula (XXIII) or carbonylchloride of formula (XXIV), in an organic solvent such as DCM, and thelike, to produce the corresponding compound of formula (XXXXI). When thecompound of formula (XXXX) is reacted with a sulfonyl chloride offormula (XXXIII) or a carbonyl chloride of formula (XXXIV), the reactionis run in the presence of an organic base such as TEA, DIEA, and thelike.

The compound of formula (XXXXI) is subjected to hydrolysis of the methylester, in the presence of an inorganic base such as sodium hydroxide,and the like, to produce the corresponding compound of formula (XXXXII).

The compound of formula (XXXXII) is coupled with a suitably substitutedamine of formula (IX), in the presence of a coupling agent such asPyBOP, and the like, in an organic solvent such as DCM, and the like, toproduce the corresponding compound of formula (If).

Compounds of formula (I), particularly those wherein X¹ and X⁴ are eachcarbonyl or sulfonyl and X² and X³ are each absent may be preparedaccording to the process outlined in Scheme 8

Accordingly, wherein A¹ is an oxo and cyano substituted cycloalkyl, anoxo and cyano substituted cycloalkenyl, an oxo and cyano substitutedcycloalkyl-alkyl, an oxo-alkyl and cyano substituted aryl or anoxo-alkyl and cyano-alkyl substituted aryl-alkyl, a known compound orcompound prepared by known methods, is reacted with a compound offormula (XV), prepared as outlined in Scheme 2, in the presence of areducing agent such as sodium cyanoborohydride, and the like, underdehydrating conditions, for example in an acid alcohol solution such asacidic methanol, to produce the corresponding compound of formula(XXXXIII).

The compound of formula (XXXXIII) is reacted with an appropriatelyselected and suitably substituted isocyanate of formula (XXII), whereinR^(3A) is as previously defined, sulfonyl chloride of formula (XXIII) orcarbonyl chloride of formula (XXIV), in an organic solvent such as DCM,and the like, to produce the corresponding compound of formula (XXXXIV).When the compound of formula (XXXXIII) is reacted with a sulfonylchloride of formula (XXIII) or a carbonyl chloride of formula (XXIV),the reaction is run in the presence of an organic base such as TEA,DIEA, and the like.

The cyano functional group on the compound of formula (XXXXIV) isreduced by known methods, for example by treatment with lithium aluminumhydride, in an organic solvent such as THF, and the like, to produce thecorresponding compound of formula (XXXXV).

The compound of formula (XXXXV) is reacted with a suitably substitutedaldehyde of formula (XXX), wherein R^(1A) is as previously defined, inthe presence of a reducing agent such as sodium cyanoborohydride, andthe like, under dehydrating conditions, for example in an acid alcoholsolution such as acidic methanol or in a solution of titaniumtetraisopropoxide in DCM, followed by addition of methanol and sodiumcyanoborohydride, to produce the corresponding compound of formula(XXXXVI).

The compound of formula (XXXXVI) is reacted with an appropriatelyselected and suitably substituted isocyanate of formula (XXXII), whereinR^(2A) is as previously defined, sulfonyl chloride of formula (XXXIII),or carbonyl chloride of formula (XXXIV), in an organic solvent such asDCM, and the like, to produce the corresponding compound of formula(Ig). When the compound of formula (XXXXVI) is reacted with a sulfonylchloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV),the reaction is run in the presence of an organic base such as TEA,DIEA, and the like.

Compounds of formula (I) wherein R¹, X¹ and R² are taken together (withthe amine nitrogen) to form an oxo substituted heterocyclyl group, maybe prepared according to the process outlined in Scheme 9.

More particularly, the compound of formula (XXIX), prepared as in Scheme5, is reacted with a suitably substituted symmetric or asymmetricanhydride, a compound of formula (XXXXVII), preferably a symmetricanhydride, in an organic solvent such as toluene, DCM, and the like, toyield the corresponding compound of formula (XXXXVIII).

The compound of formula (XXXXVIII) is heated at an elevated temperaturein the range of about 40-180° C., or treated with addition of ananhydride such as acetic anhydride, trifluoroacetic anhydride, and thelike, in an organic solvent such as methylene chloride, toluene,1,2-dichlorobenzene, and the like, to yield the corresponding compoundof formula (Ih), wherein

represents the group wherein R¹, R² and X¹ are taken together (with theamine nitrogen) to form a cyclic oxo substituted heterocyclyl.

Wherein the compound of formula (XXXXVII) is an asymmetric anhydride, (acompound of the formula R²′—C(O)—C(O)—R²″, wherein R²′0 and R²″ aredifferent), the R² group which is coupled onto the compound of formula(XXIX) may be readily determined by one skilled in the art, based on therelative reactivities of the carbonyl groups adjacent to the R²′ and R²″groups.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, HPLC, acid-baseextraction, crystallization and distillation.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved by enzymatic resolution orby using a chiral HPLC column.

To prepare the pharmaceutical compositions of this invention, one ormore compounds or salts thereof, as the active ingredient, is intimatelyadmixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed. Thus for liquid oral preparations, such as for example,suspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like; for solid oral preparations such as, forexample, powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, though other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will preferably contain per dosageunit, e.g., tablet, capsule, powder, injection, teaspoonful and thelike, from about 5 to about 500 mg of the active ingredient, althoughother unit dosages may be employed.

In therapeutic use for treating disorders of the gastrointestinal systemin mammals, the compounds of this invention may be administered in anamount of from about 0.5 to 100 mg/kg 1-2 times per day orally. Inaddition the compounds may be administered via injection at 0.1 -10mg/kg per day. Determination of optimum dosages for a particularsituation is within the capabilities of formulators.

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are meant toillustrate and suggest a method of practicing the invention. Althoughthere are other methods of practicing this invention, those methods aredeemed to be within the scope of this invention.

EXAMPLE 1 N-trityl-cis-3-aminocyclohexanecarboxylic acid

Adapting the method of K. Barlos, D. Papaioannou and D. Theodoropoulos,JOC, 1982, 47, 1324-1326, cis-3-aminocyclohexanecarboxylic acid wasprotected as the N-trityl derivative.

TMSCI (26.1 ml, 0.205 mmol) was added to a suspension ofcis-3-aminocyclohexanecarboxylic acid (29.4 g, 0.205 mmol) suspended ina 5:1 solution of CH₂Cl₂—CH₃CN (500 ml) at room temperature. The mixturewas heated at reflux for 2 hours and then allowed to cool to ambienttemperature. TEA (57.2 ml, 0.410 mmol) was added dropwise to themixture, followed immediately by portionwise addition of triphenylmethylchloride (57.2 g, 0.205 mmol). After stirring for 18 h, MeOH was addedto the mixture to give a homogeneous solution. The mixture wasevaporated down to dryness and the resultant residue partitioned betweenEt₂O and 10% citric acid (1:1, 800 ml total). The ether layer wascollected and combined with an ether extraction (150 ml) of the citricacid layer. The combined ether fractions were then extracted with 2 MNaOH (3×250 ml) and water (1×100 ml). The aqueous layers were washedwith ether (2×150 ml). After cooling to 0° C., the aqueous layer wasacidified to pH 7 with concentrated HCl and extracted with ethyl acetate(3×200 ml). The combined extracts were dried over MgSO₄ and evaporateddown to give a white foam, 67.4 g, 85% yield.

MS 384 (M⁻⁾

¹H NMR (CDCl₃) δ 0.44-0.95 (br m, 3H), 0.97-1.22 (br m, 2H), 1.30-1.48(brm, 1H), 1.53-1.79 (brm, 2H), 1.8-2.04 (brm, 1H), 2.10-2.29 (brm, 1H),6.95-7.24 (m, 9H), 7.36-7.59 (m, 6H).

EXAMPLE 2 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine

Following the procedure disclosed in GB 924961; 1959; Chem.Abstr.; 59;9883b; 1963.

3-nitrophenol (3.29 g, 23.7 mmol) in DMF (20 ml) was added dropwise to60% NaH (2.65 g, 66.2 mmol) in 30 ml DMF at 0° C., under nitrogen. Thereaction was stirred until H₂(g) evolution ceased.1-(2-chloroethyl)pyrrolidine hydrochloride (5.63 g, 33.1 mmol) was thenadded portionwise. The mixture was stirred at room temperature for 18 h.The reaction mixture was quenched with 2N NaOH (50 ml) and the desiredproduct extracted into ether (3×50 ml). The combined ether layers werewashed (2×50 ml) with water, dried over MgSO₄, and evaporated to drynessin vacuo. The residue was purified through a silica gel plug using 10%ethyl acetate/hexane to remove the impurities and then the desiredproduct was eluted off with 40% ethyl acetate/hexane containing 2% Et₃Nto yield a pale yellow oil.

MS 237 (MH⁺)

¹H NMR (CDCl₃) δ 1.78-1.88 (m, 4H), 2.55-2.66 (m, 4H), 2.94 (t, J=5.8Hz, 2H), 4.18 (t, J=5.8 Hz, 2H), 7.23-7.28 (m, 1H), 7.42 (virtual t,J=8.2 Hz, 1H), 7.75-7.76 (m, 1H), 7.80-7.83 (m, 1H).

EXAMPLE 2B 2-(2-(3-aminophenoxy)ethyl)-1-methylpyrrolidine

3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added dropwise to95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0° C., under nitrogen. Thereaction was stirred until H₂(g) evolution ceased.2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.25 g, 6.8 mmol)was then added portionwise. The mixture was stirred at room temperaturefor 18 h. The reaction mixture was quenched with 1N NaOH (50 ml) and thedesired product extracted into ether (3×50 ml). The combined etherlayers were washed (2×50 ml) with water, dried over MgSO₄, andevaporated to dryness in vacuo. The residue was purified on silica gelby flash chromatography using 2% TEA in ethyl acetate to give an oil.

MS 221 (MH⁺)

¹H NMR (CDCl₃) δ 1.46-2.31 (m, 8H), 2.34 (s, 3H), 3.08 (ddd, J=8.3, 7.6,2.4 Hz, 1H), 3.64 (br s, 2H), 3.89-4.08 (m, 2H), 6.20-6.36 (m, 3H), 7.04(t, J=8.0 Hz, 1H).

Example 2C

1-(2-(3-aminophenoxy)ethyl)piperidine

Following the procedure as described in Example 2B, 19.9 g (0.182 mol)of 3-aminophenol was converted into the title compound as a light yellowoil.

MS 221 (MH⁺)

¹H NMR (CDCl₃) δ 1.38-1.50 (m, 2H), 1.52-1.66 (m, 4H), 2.43-2.56 (m,4H), 2.75 (t, J=6.1 Hz, 2H), 3.65 (s br, 2H) 4.07 (t, J=6.1 Hz, 2H),6.22-6.35 (m, 3H), 7.04 (t, J=7.9 Hz, 1H).

EXAMPLE 3 1-(2-(3-aminophenoxy)ethyl)pyrrolidine

A mixture of 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine (3.49 g, 14.8 mmol),10% palladium on carbon (400 mg) and ethyl acetate (20 ml) was reducedunder 50 psi hydrogen for 10 h. The reaction mixture was filteredthrough Celite 545 and the product extracted into 1M HCl (3×20 ml). Theacidic layer was washed with ether (2×20 ml) and then the pH adjustedto >10 with 2M NaOH. The aqueous layer was extracted with ether (3×20ml), dried over MgSO₄ and concentrated in vacuo. The product was elutedthrough a silica gel pad (75% ethyl acetate/hexane/1% Et₃N) to yield theproduct as a pale yellow oil.

MS 207 (MH⁺)

¹H NMR (CDCl₃) δ 1.72-1.80 (m, 2H), 2.54-2.71 (m, 2H), 2.88 (t, J=8.2Hz, 2H), 3.48-3.79 (br s, 2H), 4.07 (t, J=8.2 Hz, 2H), 6.22-6.39 (m,3H), 7.05 (virtual t, J=9.1 Hz, 1H).

EXAMPLE 4N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-3-(triphenylmethylamino)cyclohexylcarboxamide

Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBop) (4.8 g, 9.3 mmol) was added to a mixture ofN-trityl-cis-3-aminocyclohexanecarboxylic acid (3.3 g, 8.4 mmol),1-(2-(3-aminophenoxy)ethyl)pyrrolidine (1.4 g, 7.0 mmol), DIEA (1.6 ml,9.3 mmol) and dichloromethane (30 ml). After stirring overnight, thecrude mixture was evaporated onto silica gel and purified by flashchromatography (20% EtOAc/2% Et₃N/hexane, then 60% EtOAc/2%Et₃N/hexane). The title compound was isolated as a white foam uponevaporation.

Yield: 3.2 g, 78%

MS 596 (MNa⁺), 574 (MH⁺), 332 (MH^(+-trt),) 243 (trt⁺).

EXAMPLE 5N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyclohexylmethylamine

LAH (220 mg, 5.8 mmol) was added to N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-(3-(triphenylmethyl)amino)cyclohexylmethyl-carboxamide(2.1 g, 3.7 mmol) in THF (10 ml) under nitrogen at ambient temperature.The reaction was refluxed for 8 h, cooled to room temperature andquenched with a saturated solution of Rochelle's salt (potassium sodiumtartrate). The precipitate was filtered away through Celite 545 leavingthe crude product as an oil upon evaporation. The residue was dissolvedin EtOAc (20 ml), washed with water (2×20 ml) and dried over MgSO₄.Evaporation of the solvent yielded the product as a white foam.

MS 582 (MNa⁺), 560 (MH⁺), 318 (MH^(+-trt),) 243 (trt⁺).

EXAMPLE 6N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cyclohexylmethyl]-4-fluorophenylcarboxamide

4-fluorobenzoyl chloride (0.34 ml, 2.9 mmol) in dichloromethane (5 ml)was added dropwise to a solution ofN-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyclohexylmethylamine(1.4 g, 2.6 mmol), triethylamine (0.40 ml, 2.9 mmol) and dichloromethane(10 ml). After 3 h the reaction was quenched with 2M NaOH (3 ml) andextracted with DCM (3×20 ml). The organic layers were combined, driedover MgSO₄ and evaporated onto silica gel in vacuo. The product waspurified by chromatography on a silica gel column, preconditioned withEt₃N, using 50% EtOAc/2% Et₃N/hexane. The product was isolated as awhite foam.

MS 682 (MH⁺), 440 (MH^(+-trt),) 243 (trt⁺).

EXAMPLE 7 N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-(3-aminocyclohexyl)methyl]-4-fluorophenylcarboxamide

10% TFA/1% triethylsilane/DCM (35 ml) was added toN-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cyclohexylmethyl]-4-fluorophenylcarboxamide(1.75 g, 2.57 mmol). Upon completion, after 3 h, the desired product wasextracted into 1 M HCI (3x 20 ml). The extracts were washed with DCM(2×20 ml) and the aqueous layer (cooled to 0° C.) made basic with NaOH.Extraction of the aqueous layer with EtOAc (3×20 ml) yielded, upondrying (MgSO₄) and evaporation, the product as a pale yellow oil.

MS 462 (MNa⁺), 440 (MH⁺).

EXAMPLE8

To a stirred solution ofN-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-amino-cyclohexyl)methyl-4-fluorophenylcarboxamide (1.0 g, 2.3 mmol) and benzaldehyde(0.26 ml, 2.5 mmol) in toluene (4 ml) was added titanium(IV)isopropoxide (0.82 ml, 2.8 mmol) under nitrogen. After 18 h, EtOH (0.8ml) was added followed by portionwise addition of sodiumtriacetoxyborohydride (0.63 g, 2.8 mmol). After an additional 4 h ofstirring, the reaction was quenched with 2M NaOH. The precipitate wasfiltered off through Celite 545, then dried over MgSO₄ and evaporated invacuo to yield crude N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(benzylamino)cyclohexyl)methyl-4-fluorophenylcarboxamide.

The crude residue (1.2 g) was taken up in DCM (4 ml), followed byaddition of trimethylacetyl chloride (0.31 ml, 2.5 mmol). The reactionwas complete in less than 2 h. The reaction was neutralized with asaturated solution of NaHCO₃, extracted with DCM (3×10 ml), dried overMgSO₄ and evaporated onto silica gel. The product was purified by flashchromatography (50% EtOAc/1% Et₃N/hexane) to yield a white foam (690mg). Addition of 1M HCl (1.2 ml, 1.2 mmol) in ether to the free base inether (5 ml) yielded the product.

MS 614 (MH⁺); HPLC (RT 4.11 min.)

EXAMPLE 9N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)cyclohexyl)methyl-N′-phenylurea

Phenylisocyanate (0.31 ml, 2.9 mmol) was added dropwise to a solution ofN-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)-cyclohexyl)methylamine (1.4 g, 2.6 mmol) in dichloromethane (5 ml). After stirringfor 18 h, the reaction mixture was evaporated onto silica gel. The titleproduct was isolated by chromatography (50% EtOAc/hexane, then 60%EtOAc/2% Et₃N/hexane) as a white foam.

MS 679 (MH⁺), 437 (MH^(+-trt),) 243 (trt⁺).

EXAMPLE 10

By the method of example 7 and 8,N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethyl)aminocyclohexyl)methyl-N′-phenylurea,benzaldehyde and trimethylaacetyl chloride were reacted to yield thetitle compound.

MS 437 (MH⁺).

EXAMPLE 11N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclohexylmethyl]-4-fluorophenylcarboxamide

To a stirred solution ofN-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide (5.3 g, 12 mmol) and3-nitrobenzaldehyde (2.0 g, 13 mmol) in DCM (30 ml) was addedtitanium(IV) isopropoxide (4.6 ml, 16 mmol) under nitrogen. After 3 h,EtOH (20 ml) was added followed by portionwise addition of sodiumcyanoborohydride (1.0 g, 16 mmol). The reaction was stirred overnight,then quenched with 2M NaOH. The resulting precipitate was filtered offthrough Celite 545, the filtrate was dried over MgSO₄ and evaporated invacuo to yield crude product.

MS 591 (MH⁺).

EXAMPLE 12

Trichloroacetyl chloride (0.93 ml, 8.3 mmol) was added to crudeN-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclohexylmethyl]-4-fluorophenylcarboxamide(4.9 g, 8.3 mmol) taken up in DCM (20 ml). The reaction was complete inless than 2 h. The reaction was neutralized with a saturated solution ofNaHCO₃, extracted into DCM (3×15 ml), dried over MgSO₄ and evaporatedonto silica gel. The product was purified by chromatography (50%EtOAc/2% Et₃N/hexane) to yield the title compound as a white foam.

MS 736 (MH⁺); HPLC (RT 4.11 min.).

EXAMPLE 13 N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis3-(benzylamino)cyclohexyl)methyl}-N′-phenylurea

By the method of example 11,N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-N′-phenylureaand benzaldehyde were converted into the title compound.

MS 543 (MH⁺).

EXAMPLE 14

By the method of example 9,N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)methyl}-N′-phenylureaand phenylisocyanate were converted into the title compound.

MS 662 (MH⁺); HPLC (RT 4.38 min.).

EXAMPLE 15

By the method of example 12,N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)methyl}-N′-phenylureaand 2-naphthalenesulfonyl chloride were converted into the titlecompound.

MS 733 (MH⁺); HPLC (RT 4.97 min.).

EXAMPLE 16

By the method of example 12,N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-cis-3-(aminocyclohexyl)methyl}-N′-phenylureaand trichloroacetyl chloride were converted into the title compound.

MS 599 (MH⁺); HPLC (RT 3.59 min.).

EXAMPLE 17 1-(2-(3-amino-2-methylphenoxy)ethyl)pyrrolidine

By the method of examples 2 and 3, 1-(2-chloroethyl)pyrrolidinehydrochloride and 2-methyl-3-nitrophenol were converted into the titlecompound.

MS 221 (MH⁺)

¹H NMR (CDCl₃) 61.75-1.86 (m, 4H), 2.05 (s, 3H), 2.62-2.67 (m, 4H), 2.92(t, J=6.0 Hz, 2H), 3.60 (br s, 2H), 4.09 (t, J=6.0 Hz, 2H), 6.33(virtual d, J=8.1 Hz, 2H), 6.95 (virtual t, J=9.1 Hz, 1H).

EXAMPLE 18 4-(2-(3-aminophenoxy)ethyl)morpholine

By the method of examples 2 and 3, 4-(2-chloroethyl)morpholinehydrochloride and 3-nitrophenol were converted into the title compound.

MS 223 (MH⁺)

EXAMPLE 19N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine

4-fluorobenzaldehyde (1.3 ml, 12 mmol) was added to a stirred solutionof 4-(2-(3-aminophenoxy)ethyl)morpholine (2.2 g, 10 mmol) in 2%AcOH/MeOH (40 ml). After 1 h, sodium cyanoborohydride (0.50 g, 12 mmol)was added portionwise to the mixture. After an additional 2 h, 2M NaOH(20ml) was added and the mixture evaporated to give a tan residue. Theresidue was partitioned between 1N HCl and ether. The acid layer waswashed 2×40 ml with ether and then adjusted to a pH >10 with NaOH. Theproduct was extracted into ethyl acetate (3×50 ml), dried over magnesiumsulfate and evaporated down to yield the title compound as a brown oil.

MS 331 (MH⁺)

¹H NMR (CDCl₃) δ 2.50-2.65 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.68-3.82(m, 4H), 4.01-4.16 (m, 3H), 4.29 (d, J=5.3 Hz, 2H), 6.18 (s, 1H),6.22-6.33 (m, 2H), 6.97-7.13 (m, 3H), 7.29-7.40 (m, 2H).

EXAMPLE 20

N-(4-fluorophenylmethyl)-4-(2-(3-amino-phenoxy)ethyl)morpholine (260 mg,0.79 mmol) and glutaric anhydride (95 mg, 0.79 mmol) were combined andrefluxed in chloroform (3 ml) overnight. To the organic solution atambient temperature was added, N-benzylphenethylamine (170 mg, 0.79mmol), DIEA (0.28 ml, 1.6 mmol) and PyBOP (420 mg, 0.80 mmol). Thesample was concentrated down upon completion (<3 h). Chromatography onsilica gel with 1% MeOH in ethyl acetate provided the title compound.

MS 638 (MH⁺); HPLC (RT 4.32 min.)

¹H NMR (CDCl₃) (approximately 1:1 mixture of rotomers) δ 1.85-2.01 (m,2H), 2.08-2.22 (m, 2H), 2.26-2.43 (m, 2H), 2.78 (t, J=7.4 Hz, 2H),2.9-3.13 (m, 2H), 3.32-3.74 (m, 6H), 3.88-4.05 (m, 4H), 4.24-4.42 (m,3H), 4.54 (s, 1H), 4.75-4.88 (m, 2H), 6.45 (s, 1H), 6.59 (t, J=6.2 Hz,1H), 6.78-7.00 (m, 3H), 7.03-7.39 (m, 13H).

EXAMPLE 21 N-(3-nitrophenyl)methyl)phenethylamine

Sodium cyanoborohydride (0.18 g, 2.7 mmol) was added to a preformedimine of phenethylamine (0.28 g, 2.3 mmol) and 3-nitrobenzaldehyde (0.38g, 2.5 mmol) in 2% AcOH-MeOH. The reaction was quenched after 4 h with asaturated solution of sodium bicarbonate and the solvent removed invacuo. The resultant residue was partitioned between water anddichloromethane (20 ml total). The aqueous layer extracted with DCM(3×20ml), the organic extracts were combined and dried over sodiumsulfate. The crude material was used without further purification.

MS 257 (MH⁺).

EXAMPLE 22N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-N′-(2-phenethyl)-1,5-pentyldiamide

A solution ofN-(4-fluorophenylmethyl)-1-(2-(3-amino-2-methylphenoxy)-ethyl)pyrrolidine (4.85 g, 14.8 mmol) and glutaric anhydride (2.02 g, 17.7mmol) in toluene (30 ml) was heated to reflux. After 12 h the reactionwas concentrated in vacuo. PyBop (430 mg, 0.81 mmol)was added to thesolution of crude N-(4-fluorophenylmethyl)-N-3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenylcarboxamidopentyric acid(330 mg, 0.74 mmol) and phenethylamine (90 mg, 0.74 mmol) in DMF (2 ml). The reaction mixture was stirred overnight, diluted with 2 M NaOH andthen extracted with ether (3×20 ml). The combined extracts were washedwith a brine solution and dried over MgSO₄. The crude material waspurified by flash chromatography on silica gel using 80% ethylacetate/2% Et₃N/hexane as eluent to yield the title compound as a brownoil.

MS 546 (MH⁺).

EXAMPLE 23

60% sodium hydride ( 3 mg, 0.07 mmol) was added to N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-N′-(2-phenethyl)-1,5-pentyldiamide (30 mg, 0.06 mmol) in DMF (1 ml). After 10 min,methyl-3-(bromomethyl)benzoate (16 mg, 0.07 mmol) was added to thestirred solution. The reaction was quenched with sodium bicarbonateafter 18 h and then extracted (3×15 ml) into ether. The title productwas isolated by semi-prep HPLC (C-18 column, 30% CH₃CN/water/0.1% TFA to60% CH₃CN/water/0.1% TFA). Note: the methyl ester was hydrolyzed underthe acidic mobile phase conditions.

MS 680 (MH⁺); HPLC (RT 3.53 min.)

EXAMPLE 24 N-(3-tert-butyldimethylsiloxyphenyl)4-fluorobenzylamine

By the method of example 19, 4-fluorobenzaldehyde (4.41 g, 35.5 mmol)and 3-aminophenol (3.60 g, 32.3 mmol) were reacted to yield a clear oil(6.75 g) upon silica gel purification (15% ethyl acetate/hexane).

MS 218 (MH⁺).

The resultant N-3-hydroxyphenyl-4-fluorobenzylamine (4.25 g, 19.6 mmol)and imidazole (1.33 g, 19.6 mmol) were combined in DMF (20 ml) andtreated with tetrabutyidimethylsilyl chloride (3.05 g, 19.6 mmol). After5 h, the reaction was diluted with saturated NaHCO₃ and extracted withether. The ether layers were combined, washed with water and dried overMgSO₄. The title product was isolated by flash chromatography (15%EA/hexane) as a clear oil (3.75 g, 58%).

MS 332 (MH⁺)

¹H NMR (CDCl₃) δ 60.12 (s, 6H), 0.81 (s, 9H), 3.84 (brs, 1H), 4.12 (s,2H), 5.96 (t, J=2.2 Hz, 1H), 6.10 (td, J=8.0, 2.2 Hz, 2H), 6.84-6.91 (m,3H), 7.16-7.21 (m, 2H).

EXAMPLE 25N-((4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide(#175)

N-(4-fluorophenyl)methyl)-N-(3-tert-butyidimethylsiloxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide (4.2 g, 6.6 mmol), prepared by method ofexample 20, in THF (10 ml) was treated with 1 M TBAF (7.3 ml, 7.3 mmol).The reaction, complete in less than 15 h, was quenched with 0.1 M HCl.The aqueous layer was extracted with ethyl acetate (3×30 ml) and theorganic layers dried over MgSO₄. The crude material was purified byflash chromatography using 50% ethyl acetate/hexane as eluent. The titlecompound was recovered as a clear oil.

MS 525 (MH⁺)

¹H NMR (CDCl₃) (approximately 1:1 mixture of rotomers) δ 1.84-2.02 (m,2H), 2.08-2.21 (m, 2H), 2.25 (t, J=7.3 Hz,1H), 2.34 (t, J=7.3 Hz, 1H),2.72-2.86 (m, 2H), 3.38-3.59 (m, 2H), 4.37 (s, 1H), 4.55 (s, 1H), 4.76(s, 1H), 4.78 (s, 1H), 6.40 (t, J=7.7 Hz, 1H), 6.52 (m, 1H), 6.77-6.93(m, 3H), 7.03-7.39 (m, 13H), 8.41 (s, 1H).

EXAMPLE 26

ToN-(4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide (75 mg, 0.14 mmol) in THF (1 ml) was added1-(2-hydroxyethyl) piperazine (22 mg, 0.17 mmol), tri-n-butylphosphine(0.14 ml, 0.57 mmol), and ADDP (86 mg, 0.34 mmol). After 18 h thereaction was diluted with a solution of saturated sodium bicarbonate andthen extracted into ethyl acetate (3 ×15 ml). The combined organiclayers were dried over MgSO₄ and evaporated down to an oil. The titleproduct was isolated by semi-prep HPLC (C-18 column, 30%CH₃CN/water/0.1% TFA to 60% CH₃CN/water/0.1% TFA).

MS 637 (MH⁺); HPLC (RT 3.34 min.).

EXAMPLE 27N-[3-(2-(4-morpholino)ethoxy)phenyl]-N′-(2-phenethyl)-N′-benzyl-1,4-butyldiamide

Applying the procedure used in Example 20, with substitution of4-(2-(3-aminophenoxyethyl) morpholine and succinic anhydride forN-(4-fluorophenylmethyl) -4-(2-(3-aminophenoxy)ethyl)morpholine andglutaric anhydride respectively, yielded the title compound as a whitesolid.

MS 516 (MH⁺)

EXAMPLE 28

N-[3-(2-(4-morpholino)ethoxy)phenyl]-N′-(2-phenethyl)-N′-benzyl-1,4-butyidiamide(0.39 g, 0.75 mmol) was dissolved in a solution of sodium borohydride(0.14 g, 3.8 mmol) in THF (4 mL). Acetic acid (0.22 ml, 3.75 mmol) wasslowly added to the reaction mixture at 0° C. After 18 h, the reactionwas quenched with 1N HCl, neutralized with saturated sodium bicarbonateand the THF layer collected. The organic layer was dried over MgSO₄,filtered and then treated with phenyl isocyanate (0.080 ml, 0.75 mmol)to yield crude solid product. The crude material was purified by flashchromatography using 50% ethyl acetate/hexane as eluent. The titlecompound was recovered as a clear oil.

MS 621 (MH⁺);

¹H NMR (CD₃OD) (approximately 1:1 mixture of rotomers) δ 1.72-1.97 (m,2H), 2.25 (t, J=6.8 Hz, 1H), 2.45 (t, J=6.8 Hz, 1H), 2.73-2.94 (m, 2H),3.18-3.42 (m, 2H), 3.48-3.91 (m, 10H), 3.97-4.15 (m, 2H), 4.40 (t, J=4.9Hz, 2H), 4.49 (s, 1H), 4.63 (s, 1H), 6.89-7.06 (m, 4H), 7.09-7.48 (m,15H).

EXAMPLE 29 2,2-dimethylpropylbenzylamine

Step A: N-3-chlorobenzyltrimethylacetamide

3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise totrimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et₃N (3.5 ml, 25 mmol)in DCM (25 ml). After two hours, the reaction mixture was washed with 1N HCl and the organic layer collected and dried over MgSO₄.N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as awhite solid, 3.95 g,

MS 192 (MH⁺).

Step B:

N-benzyltrimethylacetamide (2.35 g, 12.3 mmol) in THF (10 ml) wasrefluxed with 1M borane-tetrahydrofuran (13.5 ml) for 15 hours. Thereaction was quenched with 1N HCl, washed with ether, and the aqueouslayer adjusted to a pH>10. The aqueous layer was extracted with EtOAcand the organic layers combined and dried over MgSO₄.

The title compound may be alternatively be prepared according to theprocedure described in Overman, Larry E.; Burk, Robert M.; TELEAY;Tetrahedron Lett.; 25; 16; 1984; 1635-1638

EXAMPLE 30

EDCI-Mel (0.33 g, 1.1 mmol) was added toN-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine (0.27 g,0.83 mmol) (Prepared in Example 19), and Fmoc-L-Phe-OH (0.39 g, 1.0mmol) in CHCl₃ (15 mL). After 8 h, the reaction was diluted with asaturated solution of NaHCO₃, extracted with DCM and dried over MgSO₄.The desired product was isolated by flash chromatography (50-100%EA/hexane) to yield a white solid.

MH+700.

EXAMPLE 31

The product prepared in Example 29, (31 mg, 0.044 mmol) was dissolved inDCM (1 mL) and deprotected with piperidine (7.4 μl, 0.082 mmol) to yielda white solid upon evaporation.

MH+478.

The crude product was then dissolved along with benzaldehyde (16μl, 0.16mmol) in 2% AcOH/MeOH (1 ml). To this solution was added NaBH₃CN (20 mg,0.32 mmol) in two portions. After 1 h, the solvent was evaporated andthe residue partitioned between 1N HCl and ether. The aqueous layer waswashed with ether, adjusted to pH˜10 with 2N NaOH and extracted withDCM. The organic layer was dried over MgSO₄ and evaporated down.Hydrocinnamoyl chloride (12 μl, 0.08 mmol) was then added to the residuedissolved in DCM (2 ml) and DIEA (16 μl, 0.09 mmol). The title compoundwas isolated by semi-prep HPLC as the TFA salt.

MH+700; HPLC (RT 5.16 mins).

EXAMPLE 32

4-(2-(3-amino-phenoxy)ethyl)morpholine (389 mg, 1.75 mmol) and methyl3-bromomethylbenzoate (482 mg, 2.1 mmol) were reacted in CHCl₃ (5 mL),that contained Et₃N (293 μl, 2.1 mmol). The reaction was refluxed for 16h, until completion,as evidenced by disappearance of the startinganiline derivative on TLC (Rf 0.5 for product, ethyl acetate eluent)).

MS (MH+) 371

The reaction mixture was cooled and then treated with Et₃N (293 μl, 2.1mmol) and 4-fluorobenzoyl chloride (207 μl, 1.75 mmol). Upon completion,the reaction mixture was quenched with 1N NaOH and extracted 3 timeswith DCM. The organic layer was dried over MgSO₄ and evaporated downonto silica gel. The title compound was isolated by flash chromatography(gradient from 80% EA/hexane to 100% EA) to yield a white solid.

MS (MH+) 493

EXAMPLE 33

The compound prepared in Example 31 (375 mg, 0.82 mmol) was refluxed ina mixture of 10% NaOH/EtOH (30 ml). After 2 h, the EtOH was evaporatedunder vacuum. The residue was diluted with 2N NaOH and washed withether. The aqueous layer was then acidified to pH 1 with concentratedHCl and extracted with DCM. The organic layer was dried over MgSO4 andevaporated down. The residue was dissolved in DCM (10 mL) andpartitioned into ten aliquots. One aliquot was treated withphenethylamine (12 mg, 0.10 mmol) and EDCI-Mel (29 mg, 0.10 mmol). After16 h, the reaction mixture was washed 2×with water and evaporated downto yield a brown residue. The title compound was isolated by semi-prepHPLC (reverse phase, C-18) as the TFA salt.

MH+582; HPLC (RT 3.41 mins).

EXAMPLE 34 N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine

4-(2-(3-aminophenoxy)ethyl)morpholine (2.15 g, 9.67 mmol) and3-cyanocyclopentanone (1.06 g, 9.67 mmol) (prepared according to theprocess decsribed by Della, E.; Knill, A.; Aust. J Chem.; 47; 10; 1994;1833-1842) were combined in 1% AcOH/MeOH (50ml). To this solution wasadded NaBH₃CN (925 mg, 14.5 mmol) in portions. After 12 h, the solventwas evaporated off and the residue partitioned between saturated NaHCO₃and ethyl acetate. The aqueous layer was extracted with ethyl acetate,the combined organic layers were dried over MgSO₄ and evaporated down.The title compound was purified by flash chromatography with ethylacetate as the eluent, 2.1 g

MS (MH+) 316.

EXAMPLE 35

Phenylisocyanate (0.65 ml, 5.9 mmol) was added to N-3-cyanocyclopentyl4-(2-(3-amino-phenoxy)ethyl)morpholine (1.88 g, 5.95 mmol) partiallydissolved in THF (25 ml) at room temperature. After 15 h, crude materialwas placed on a silica gel column and eluted with ethyl acetate to give680 mg of a yellow oil.

MS (MH+) 435.

EXAMPLE 36

The product prepared in Example 34 (0.65 g, 1.5 mmol) dissolved in THF(10 ml) was added to 1M LAH (4.5 ml) at −78° C. and allowed to warm toroom temperature. After 15 h, the reaction was quenched with a saturatedsolution of Rochelle's salt (potassium sodium tartrate). The precipitatewas filtered away through Celite 545 to yield the crude product as anoil upon evaporation. The residue was dissolved in EtOAc, washed withwater and dried over MgSO₄. Evaporation of the solvent yielded theproduct as an oil.

(MH+) 439

EXAMPLE 37

Sodium cyanoborohydride (34 mg, 0.54 mmol) was added to the productprepared in Example 35 (78 mg, 0.18 mmol) and 3-chlorobenzaldehyde (40μl, 0.36 mmol) in 1% AcOH/MeOH (2 ml). After 6 hours the reaction wasacidified with 1N HCl, then neutralized with 2N NaOH and extracted intodichloromethane.

(MH+) 563.

The organic layer was dried over MgSO₄, cooled to 0° C. and then treatedwith trichloroacetyl chloride (20 μl, 0.18 mmol). The final product wasisolated by flash chromatography (ethyl acetate).

(MH+) 707

EXAMPLE 38

N-trityl-cis-3-aminocyclohexanecarboxylic acid (13.1 g, 34 mmol) wasadded to a solution of PyBop (17.7 g, 34 mmol) and DIEA (11.8 ml, 68mmol) in DCM (70 mL) and stirred for 10 minutes.1-(2-(3-aminophenoxy)ethyl)piperidine (6.8 g, 30.9 mmol) in DCM (30 mL)was added to the reaction mixture over the course of 20 mins. Thecoupled product was purified by flash chromatography (25% ethylacetate/1% Et₃N/hexane) and evaporated down to yield a white foam.

The foam was dissolved in THF (100 mL), treated with LAH (1.3 g, 34mmol)and refluxed for 7 hrs. Upon cooling, the reaction mixture wasalternately quenched with NaOH and water to yield a granular solid. Theheterogenous reaction mixture was then filtered through Celite 545. Thereduced product was extracted into ether from water. The combinedorganic layers were dried over MgSO₄ and evaporated to dryness.

The crude product and Et₃N (4.7 ml, 34 mmol) were dissolved in DCM (100mL). 4-fluorobenzoyl chloride (4.0 ml, 34 mmol) of was added dropwise tothis solution. After 2 hours the reaction mixture was evaporated ontosilica gel and then purified by flash chromatography (20% ethylacetate/1% Et₃N/hexane) to yield the title compound.

EXAMPLE 39

The compound prepared as in Example 38, was dissolved in 20% TFA/1%TES/DCM and stirred for 1 hr. The reaction mixture was evaporated downto dryness. The crude material was partitioned between ether and 1N HCl.The aqueous solution was washed twice with ether, cooled to 0° C. andthe pH adjusted to 12 with NaOH. The deprotected amine was extractedinto DCM and dried over MgSO₄.

Following the procedure as described in Example 8, the deprotectedamine, 3-chlorobenzaldehyde and trichloroacetyl chloride were reacted toyield the title compound. The enantiomers were separated using aChiralpak AD HPLC column.

EXAMPLE 40

N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide(83 mg, 0.18 mmol) and 3,3-dimethylglutaric anhydride (28mg, 0.20 mmol)were combined and heated at 90° C. in toluene (2 mL) for two hours. Thereaction mixture was concentrated in vacuo and purified by semi-prepHPLC (C18 column, acetonitrile/water/0.1% TFA) to yield the titlecompound.

EXAMPLE 41

N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide(83mg, 0.18 mmol) and phthalic anhydride (30mg, 0.20 mmol) weredissolved in toluene (2 mL). The reaction was heated at 90° C. for twohours. To the reaction was then added acetic anhydride (0.2 ml, 2.1mmol) and the reaction refluxed for an additional 15 hours. The reactionmixture was concentrated in vacuo and purified by semi-prep HPLC (C18column, acetonitrile/water/0.1% TFA) to yield the title compound as awhite solid.

EXAMPLE 42 IN VITRO TESTING

Motilin Receptor Binding

Rabbit colon was removed, dissected free from the mucosa and serosa, anddiced into small pieces. The muscle tissue was homogenized in 10 volumesof 50 mM Tris-Cl, 10 mM MgCl₂, 0.1 mg/ml bacitracin, and 0.25 mMPeflabloc, at pH 7.5 in a Polytron (29000 rpm, 4×15 seconds). Thehomogenate was centrifuged at 1000× g for 15 minutes and the supernatantdiscarded. The pellet was washed twice before being suspended inhomogenizing buffer. The crude homogenate was resuspended through a 23gauge needle before storing at 80° C. In a total volume of 0.5 ml, thebinding assay contained the following components: buffer (50 mM Tris-Cl,10 mM MgCl₂, 1 mM EDTA, 15 mg/ml BSA, 5 mg/ml of pepstatin, leupeptin,aprotinin, and 0.15 mg/ml bacitracin), I¹¹²⁵ radio-labeled porcinemotilin (50000-70000cpm; specific activity 2000 Ci/mmole), testcompound, and membrane protein. After 60 minutes at 30° C., the sampleswere cooled in ice, centrifuged in the cold at 13000× g for 1 minute.The pellet was washed twice with 1 ml of cold saline, the supernatantwas aspirated, and the pellet at the bottom of the tube counted in agamma counter. Non-specific binding was determined by the inclusion of 1mM of unlabeled motilin. IC₅₀ values were determined from Kaleidographcurves.

EXAMPLE 43 IN VITRO TESTING

Human Antrum Tissue

Human antrum tissue from Analytical Biological Services (Wilmington,Del.) was prepared as a motilin receptor preparation in the followingmanner. The muscle tissue was homogenized in 10 volumes of 50 mMTris-Cl, 1 mM MgCl₂, 0.1 mg/ml bacitracin, and 0.25 mM Peflabloc, pH7.5) in a Polytron (29000 rpm, 4×15 seconds). The homogenate wascentrifuged at 1000× g for 15 minutes and the supernatant discarded. Thepellet was washed twice before being suspended in homogenizing buffer.The crude homogenate was resuspended through a 23 gauge needle beforealiquoting and storing at −80° C. The human cloned receptor was preparedfrom HEK 293 cells overexpressed with the motilin receptor. Cell pelletswere thawed and resuspended in 2-3 volumes of homogenizing buffer (10 mMTris-Cl, 0.2 mM MgCl₂, 5 mM KCl, 5 μg/ml aprotinin, leupeptin, andpepstatin A, and 50 μg/ml bacitracin, pH 7.5) and allowed to sit on icefor 15-20 minutes. The suspension was homogenized on ice in a Douncetype homogenizer using 15 strokes. Sucrose and EDTA were added to afinal concentration of 0.25M and 1 mM, respectively, and mixed with afew additional strokes. The material was centrifuged at 400× g for 5minutes, and the supernatant saved. The pellet was re-resuspended twicewith 5 ml homogenizing buffer and rehomogenized as before, and thesupernatants combined. The supernatant was centrifuged at 100000× g for1 hour. The pellet is retained and resuspended with 5 ml of homogenizingbuffer through a 19 g and 25 g needle. The suspension is aliquoted andstored at −80° C. until used. The binding assay contains the followingcomponents (50 mM HEPES, 5 mM MgCl₂, and 1 mM EGTA, pH 7.0, 15mg/ml BSA,10μg/ml aprotinin, leupeptin, and pepstatin A, 0.25 mg/ml bacitracin,and 10 mM benzamidine), 125I-radiolabelled porcine motilin (50000-70000cpm; specific activity 2000 Ci/mmol), test compound, and membraneprotein. After 60 minutes at 30° C., the samples are placed on ice andcentrifuged for 1 minute at 13000× g. The pellet is washed twice with 1ml cold saline, and after removal of the final supematant, the pellet atthe bottom of the tube is counted in a gamma counter. Non-specificbinding is measured by the inclusion of 1 μgM unlabelled motilin. IC₅₀values were determined from Kaleidograph curves.

125I-Motilin Binding to Human Antral Stomach Membranes and the HumanCloned Receptor:

-   -   Human Antrum IC₅₀ (nM) 1.0±0.1    -   Human Cloned Receptor IC₅₀ (nM) 3.55±0.05

EXAMPLE 44 IN VIVO TESTING

Rabbit Tissue Bath Procedure

One New Zealand White rabbit (Covance) of either sex was euthanized withan IV injection of Sleepaway. The duodenum was quickly excised, thelumen rinsed with saline to clean, and the tissue placed in cold,aerated (95% 02- 5% CO₂) Tyrodes buffer (NaCl 136.9mM, KCl 2.7 mM, CaCl₂1.8 mM, MgCl₂ 1.04 mM, NaH₂PO₄ 0.42 mM, NaHCO₃ 11.9 mM, Glucose 5.55 mM,pH 7.4). The duodenum, being kept moist at all times, was cleaned of anyexcess mesenteric tissue, and then cut into 3 cm segments starting atthe proximal end. Sixteen tissue segments were usually prepared fromeach duodenum. These segments were tied on both ends with 3-0 silksuture (Ethicon). One end of the tissue was attached to an S-hook on acustom made glass support rod (Crown Glass Co., Somerville) and the rodplus tissue were placed in a 15 ml isolated tissue bath (Radnoti). Theother end of the glass rod was attached to a Grass Force DisplacementTransducer FT03. The tissue was maintained in room temperature Tyrodesbuffer pH 7.4 and continually gassed with 95% O²- 5% CO₂. The tissueswere adjusted to 1.0 g resting tension and maintained at that tensionthroughout the equilibration period. An MI2 Tissue Bath Computer wasused to record and analyze data.

The tissues were washed twice during a 30 minute equilibration periodand readjusted to 1 g resting tension as necessary. After equilibrationthe tissues were challenged with 3 μM Carbachol (CarbamoylcholineChloride-Sigma). After maximal contraction was attained, the tissueswere washed 3 times with Tyrodes. The tissues were allowed a 20 minuteresting/equilibration period, during which time they were washed onceand readjusted to 1 g resting tension. The tissues were challenged asecond time with 3 μM Carbachol, and this contraction was considered asmaximal, or 100% contraction. The tissues were washed 3 times,equilibrated for 10 minutes, washed again and readjusted to 1 g restingtension. Vehicle or test compound in 30% DMSO-50 mM HEPES was addeddirectly to the bath and the tissues were incubated for 20 minutes. Testcompounds and vehicle were run in duplicate. The tissues were thenchallenged with 3 nM Porcine Motilin (Bachem) and when maximumcontraction was attained another 3 μM aliquot of Carbachol was added tosee if the test compound inhibited this contraction.

The percent inhibition by test compound of the motilin inducedcontraction was calculated by first determining the ratio of the vehiclecontractions with Motilin compared to the Carbachol contractions. ThisTissue Adjustment Factor (TAF) was used to determine the value for thepotential uninhibited contraction with Motilin for each tissue. Thepercent inhibition was then determined by dividing the actual Motilincontraction in treated tissues by the potential uninhibited contractionand subtracting this number from 1. IC₅₀ values were determined bygraphing results with Kaleidograph graphing program.

Tables 18 and 19 below list molecular weight, % Inhibition and IC₅₀values measured for select compounds of the present invention. TABLE 18Rabbit Colon Human Antrum Tissues Mol. Wt.* % Inh IC₅₀ % Inh IC₅₀ IC₅₀ID Cal'd (MH⁺) @ 1 mM (μM) @ 1 μM (μM) (μM) 1 621 621 35 2 656 656 9 3620 620 35 4 624 624 75 0.69 5 635 635 40 6 634 634 24 7 638 638 42 8545 545 18 9 580 580 27 10 544 544 29 11 548 548 0 12 594 594 4 13 558558 21 14 562 562 25 15 531 531 21 16 566 566 21 17 530 530 12 18 534534 0 19 545 545 5 20 580 580 8 21 544 544 34 22 548 548 23 23 607 60748 24 642 642 6 25 606 606 23 26 621 621 22 27 656 656 22 28 620 620 1329 624 624 18 30 559 559 17 31 594 594 39 32 558 558 12 33 562 562 16 34573 573 7 35 608 608 17 36 572 572 32 37 576 576 11 39 709 707 4 40 662662 11 41 677 677 58 42 627 627 50 43 675 675 74 0.73 44 697 697 4 45692 692 67 1.16 46 737 737 32 47 723 721 23 48 637 637 67 0.656 49 817817 37 50 757 757 32 51 711 711 73 0.65 52 661 661 45 53 709 709 52 54731 731 42 55 726 726 48 56 771 771 27 57 733 733 15 58 706 705 38 59757 755 23 60 757 755 65 0.66 61 718 717 55 62 756 755 58 63 723 721 5564 738 737 32 65 733 732 80 0.035 0.027 66 757 755 39 67 688 687 750.957 68 689 688 73 0.66 69 572 572 0 70 547 547 0 71 643 643 43 72 598597 40 73 549 549 25 74 693 693 29 75 633 633 19 76 587 587 26 77 537537 19 78 585 585 10 79 607 607 39 80 602 602 34 81 647 647 56 82 783783 0 83 723 723 3 86 697 697 16 90 692 691 95 0.49 >0.3 91 601 600 3692 760 758 80 93 736 735 100 0.09 0.0205 94 741 740 28 95 726 724 51 96759 758 71 1.68 >.03 97 721 720 56 98 760 758 75 0.76 99 760 758 620.572 100 709 708 78 101 774 774 59 102 729 729 47 103 734 734 2 104 712712 30 105 664 664 80 0.39 0.03 106 714 714 69 1.05 107 820 820 29 108676 676 70 0.815 109 760 760 27 110 718 718 35 111 726 724 72 0.88 112740 740 70 0.48 113 695 695 51 114 700 700 49 115 678 678 26 116 630 63061 0.772 117 680 680 17 118 726 726 58 119 786 786 22 120 642 642 690.954 121 684 684 37 122 691 690 64 0.84 123 736 736 8 124 640 640 700.904 125 665 665 25 128 624 624 75 0.23 129 638 638 90 0.058 130 610610 8 131 623 622 19 132 658 658 10 133 672 672 6 134 626 626 0 135 694694 8 136 672 672 43 137 644 644 30 138 582 582 36 139 586 586 13 140638 638 45 141 672 672 21 142 670 670 17 143 596 596 0 144 638 638 54145 590 590 35 146 654 654 32 147 688 688 61 0.49 148 622 622 19 149 699699 27 150 680 680 0 151 713 712 1 152 700 700 0 153 636 636 89 0.0810.03 154 692 692 62 0.41 155 676 676 34 156 554 554 18 157 642 642 16158 601 600 37 159 652 652 83 0.275 160 652 652 61 0.96 161 664 664 22162 672 672 85 0.178 0.021 163 658 658 85 0.174 0.019 164 624 624 840.194 0.048 165 624 624 63 0.55 166 636 636 23 167 674 674 42 168 640640 36 169 638 638 97 0.046 0.24 170 638 638 81 0.163 0.185 171 650 65063 0.462 0.23 172 688 688 40 173 654 654 84 0.29 0.28 174 692 691 0 175525 525 0 176 636 636 32 177 640 640 52 >1.0 178 624 624 100 0.07 0.015179 637 637 85 0.24 0.023 180 622 622 99 0.014 0.011 181 596 596 1000.093 0.012 182 636 636 94 0.022 0.053 183 661 661 2 184 711 711 6 185671 671 0 186 722 722 0 187 610 610 100 0.229 188 650 650 100 0.2470.092 189 652 652 70 0.3 190 666 666 99 0.2 0.067 191 622 622 27 192 638638 15 193 650 650 7 194 596 596 23 195 624 624 62 196 636 636 100 0.0060.004 197 667 667 85 0.009 0.0076 198 672 672 100 0.107 199 691 690 910.1 200 690 690 92 0.041 201 657 657 93 0.057 0.0168 202 691 690 1000.33 0.23 203 649 649 98 0.24 204 662 662 89 0.029 0.003 205 683 683 760.1 206 688 688 60 0.77 207 636 636 87 0.064 208 734 733 91 0.009 0.048209 724 722 84 0.059 0.021 210 689 688 90 0.086 0.024 211 720 719 1000.014 0.072 212 710 708 89 0.058 0.036 213 675 674 84 0.058 0.027 214614 614 95 0.029 0.024 215 680 680 100 0.084 216 600 600 100 217 634 63498 218 661 660 98 0.024 0.035 219 706 705 98 0.0076 220 636 636 92 0.042221 598 598 94 223 707 705 100 0.041 224 672 671 98 0.039 225 611 611 930.021 226 648 648 100 0.032 0.009 227 683 682 100 0.025 228 650 650 1000.025 229 614 614 100 0.01 230 614 614 100 0.072 231 661 660 88 0.13 232698 698 62 233 650 650 89 0.17 234 652 652 86 0.218 235 662 61 236 72453 237 662 96 0.168 238 724 98 0.097 239 724 0.073 240 724 >0.70 241 72814 242 704 36 243 728 35 244 698 42 245 758 40 246 678 73 247 726 41 248704 86 0.760 249 716 22 250 642 0 251 604 0 252 636 15 253 600 30 254606 25 255 655 22 256 600 27 257 586 0 258 580 34 259 665 17 260 644 30261 654 0 262 550 18 263 655 11 264 570 6 265 638 67 266 598 5 267 62421 268 598 17*For compounds containing chlorine, listed Mol. Wt. values are providedfor the most abundant isotope.

TABLE 19 Cal'd Mol. % Inh @ 1 mM % Inh @ 1 mM ID Wt. MW (MH⁺) (Rabbitcolon) (Human antrum) 38 577.4 576 22 84 542.7 543 12 85 577.2 577 28 87611.6 611 22 88 592.8 593 0 89 561.7 562 3 222 619.8 620 83 83

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-35. (canceled)
 36. A method of treating a motilin receptor associatedcondition or disorder, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thecompound of claim
 1. 37. The method of claim 33, wherein the motilinreceptor associated condition or disorder is selected from the groupconsisting of gastrointestinal reflux disorders, eating disordersleading to obesity and irritable bowel disorder.
 38. A method oftreating a condition selected from the group consisting ofgastrointestinal reflux disorders, eating disorders leading to obesityand irritable bowel disorder in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 1.